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| Title: |
Prospective study of grapefruit intake and risk of breast cancer in postmenopausal women: the Multiethnic Cohort Study. |
| Author(s): |
Monroe KR, Murphy SP, Kolonel LN, Pike MC. |
| In vitro and in vivo studies have shown that cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of oestrogens. There is evidence that grapefruit, an inhibitor of CYP3A4, increases plasma oestrogen concentrations. Since it is well established that oestrogen is associated with breast cancer risk, it is plausible that regular intake of grapefruit would increase a woman's risk of breast cancer. We investigated the association of grapefruit intake with breast cancer risk in the Hawaii-Los Angeles Multiethnic Cohort Study, a prospective cohort that includes over 50 000 postmenopausal women from five racial/ethnic groups. A total of 1657 incident breast cancer cases were available for analysis. Grapefruit intake was significantly associated with an increased risk of breast cancer (relative risk=1.30, 95% confidence interval 1.06-1.58) for subjects in the highest category of intake, that is, one-quarter grapefruit or more per day, compared to non-consumers (P(trend)=0.015). An increased risk of similar magnitude was seen in users of oestrogen therapy, users of oestrogen+progestin therapy, and among never users of hormone therapy. Grapefruit intake may increase the risk of breast cancer among postmenopausal women.British Journal of Cancer (2007) 97, 440-445. doi:10.1038/sj.bjc.6603880 www.bjcancer.com Published online 10 July 2007. |
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Title:
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Intakes of calcium and vitamin d and breast cancer risk in women. |
| Author(s): |
Lin J, Manson JE, Lee IM, Cook NR, Buring JE, Zhang SM. |
| BACKGROUND: Animal data suggest the potential anticarcinogenic effects of calcium and vitamin D on breast cancer development. However, epidemiologic data relating calcium and vitamin D levels to breast cancer have been inconclusive. METHODS: We prospectively evaluated total calcium and vitamin D intake in relation to breast cancer incidence among 10 578 premenopausal and 20 909 postmenopausal women 45 years or older who were free of cancer and cardiovascular disease at baseline in the Women's Health Study. Baseline dietary intake was assessed by a food frequency questionnaire. We used Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals. RESULTS: During an average of 10 years of follow-up, 276 premenopausal and 743 postmenopausal women had a confirmed diagnosis of incident invasive breast cancer. Higher intakes of total calcium and vitamin D were moderately associated with a lower risk of premenopausal breast cancer; the hazard ratios in the group with the highest relative to the lowest quintile of intake were 0.61 (95% confidence interval, 0.40-0.92) for calcium (P = .04 for trend) and 0.65 (95% confidence interval, 0.42-1.00) for vitamin D intake (P = .07 for trend). The inverse association with both nutrients was also present for large or poorly differentiated breast tumors among premenopausal women (P |
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Title:
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One year pre-post intervention follow-up of psychological, immune, endocrine and blood pressure outcomes of mindfulness-based stress reduction (MBSR) in breast and prostate cancer outpatients. |
| Author(s): |
Carlson LE, Speca M, Patel KD, Faris P. |
| OBJECTIVES: This study investigated the ongoing effects of participation in a mindfulness-based stress reduction (MBSR) program on quality of life (QL), symptoms of stress, mood and endocrine, immune and autonomic parameters in early stage breast and prostate cancer patients. METHODS: Forty-nine patients with breast cancer and 10 with prostate cancer enrolled in an eight-week MBSR program that incorporated relaxation, meditation, gentle yoga and daily home practice. Demographic and health behaviors, QL, mood, stress symptoms, salivary cortisol levels, immune cell counts, intracellular cytokine production, blood pressure (BP) and heart rate (HR) were assessed pre- and post-intervention, and at 6- and 12-month follow-up. RESULTS: Fifty-nine, 51, 47 and 41 patients were assessed pre- and post-intervention and at 6- and 12-month follow-up, respectively, although not all participants provided data on all outcomes at each time point. Linear mixed modeling showed significant improvements in overall symptoms of stress which were maintained over the follow-up period. Cortisol levels decreased systematically over the course of the follow-up. Immune patterns over the year supported a continued reduction in Th1 (pro-inflammatory) cytokines. Systolic blood pressure (SBP) decreased from pre- to post-intervention and HR was positively associated with self-reported symptoms of stress. CONCLUSIONS: MBSR program participation was associated with enhanced quality of life and decreased stress symptoms, altered cortisol and immune patterns consistent with less stress and mood disturbance, and decreased blood pressure. These pilot data represent a preliminary investigation of the longer-term relationships between MBSR program participation and a range of potentially important biomarkers. |
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Title:
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Serum calcium and breast cancer risk: results from a prospective cohort study of 7,847 women. |
| Author(s): |
Almquist M, Manjer J, Bondeson L, Bondeson AG. |
| Experimental and epidemiological studies suggest that calcium-regulating hormones-parathyroid hormone (PTH) and vitamin D-may be associated with breast cancer risk. No prospective cohort study has investigated the association between pre-diagnostic calcium levels and subsequent risk of breast cancer. We have examined this in a cohort of 7,847 women where serum calcium levels and established risk factors for breast cancer had been assessed at baseline. During a mean follow-up of 17.8 years, 437 incident breast cancer cases were diagnosed. Incidence of breast cancer was calculated in different quartiles of serum calcium levels and a Cox's proportional hazards analysis was used to obtain corresponding relative risks (RR), with a 95% confidence interval (CI), adjusted for potential confounders. In premenopausal women, serum calcium levels were inversely associated with breast cancer risk in a dose-response manner. The adjusted RR (95% CI) of breast cancer was in the 2nd calcium quartile 0.91 (0.65-1.30), in the 3rd quartile 0.89 (0.60-1.31), and in the 4th quartile 0.56 (0.32-0.98), as compared to the 1st calcium quartile. In postmenopausal overweight women (BMI > 25), breast cancer risk was higher in calcium quartiles 2-4 as compared to the 1st quartile. Our findings may have implications for primary prevention of breast cancer and for the management of asymptomatic primary hyperparathyroidism. |
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Title:
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The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice. |
| Author(s): |
Bachmeier B, Nerlich AG, Iancu CM, Cilli M, Schleicher E, Vene R, Dell'Eva R, Jochum M, Albini A, Pfeffer U. |
| Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitroand in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA-MB-231 cells in correlation with reduced activation of the survival pathway NFkappaB, as a consequence of diminished IotakappaB and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NFkappa B activity and transcriptional downregulation of AP-1. NFkappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NFkappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NFkappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible. Copyright 2007 S. Karger AG, Basel. |
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Title:
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Vitamin D and prevention of breast cancer: pooled analysis. |
| Author(s): |
Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, Newmark H, Holick MF, Garland FC. |
| BACKGROUND: Inadequate photosynthesis or oral intake of Vitamin D are associated with high incidence and mortality rates of breast cancer in ecological and observational studies, but the dose-response relationship in individuals has not been adequately studied. METHODS: A literature search for all studies that reported risk by of breast cancer by quantiles of 25(OH)D identified two studies with 1760 individuals. Data were pooled to assess the dose-response association between serum 25(OH)D and risk of breast cancer. RESULTS: The medians of the pooled quintiles of serum 25(OH)D were 6, 18, 29, 37 and 48 ng/ml. Pooled odds ratios for breast cancer from lowest to highest quintile, were 1.00, 0.90, 0.70, 0.70 and 0.50 (p trend<0.001). According to the pooled analysis, individuals with serum 25(OH)D of approximately 52 ng/ml had 50% lower risk of breast cancer than those with serum <13 ng/ml. This serum level corresponds to intake of 4000 IU/day. This exceeds the National Academy of Sciences upper limit of 2000 IU/day. A 25(OH)D level of 52 ng/ml could be maintained by intake of 2000 IU/day and, when appropriate, about 12 min/day in the sun, equivalent to oral intake of 3000 IU of Vitamin D(3). CONCLUSIONS: Intake of 2000 IU/day of Vitamin D(3), and, when possible, very moderate exposure to sunlight, could raise serum 25(OH)D to 52 ng/ml, a level associated with reduction by 50% in incidence of breast cancer, according to observational studies. |
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Title:
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Dietary fibre and risk of breast cancer in the UK Women's Cohort Study. |
| Author(s): |
Cade JE, Burley VJ, Greenwood DC. |
| BACKGROUND: Reports of relationships between dietary fibre intake and breast cancer have been inconsistent. Previous cohort studies have been limited by a narrow range of intakes. METHODS: Women who developed invasive breast cancer, 350 post-menopausally and 257 pre-menopausally, during 240 959 person-years of follow-up in the UK Women's Cohort Study (UKWCS) were studied. This cohort has 35 792 subjects with a wide range of exposure to dietary fibre with intakes of total fibre in the lowest quintile of <20 g/day up to >30 g/day in the top quintile. Fibre and breast cancer relationships were explored using Cox regression modelling adjusted for measurement error. Effects of fibre, adjusting for confounders were examined for pre- and post-menopausal women separately. RESULTS: In pre-menopausal, but not post-menopausal women a statistically significant inverse relationship was found between total fibre intake and risk of breast cancer (P for trend = 0.01). The top quintile of fibre intake was associated with a hazard ratio of 0.48 [95% confidence interval (CI) 0.24-0.96] compared with the lowest quintile. Pre-menopausally, fibre from cereals was inversely associated with risk of breast cancer (P for trend = 0.05) and fibre from fruit had a borderline inverse relationship (P for trend = 0.09). A further model including dietary folate strengthened the significance of the inverse relationship between total fibre and pre-menopausal breast cancer. CONCLUSIONS: These findings suggest that in pre-menopausal women, total fibre is protective against breast cancer; in particular, fibre from cereals and possibly fruit. |
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Title:
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Beta glucan induces proliferation and activation of monocytes in peripheral blood of patients with advanced breast cancer. |
| Author(s): |
Demir G, Klein HO, Mandel-Molinas N, Tuzuner N. |
| AIM: Glucans are glucose polymers that constitute a structural part of fungal cell wall. They can stimulate the innate immunity by activation of monocytes/macrophages. In human studies it has been shown that beta glucan has an immunomodulatory effect and can increase the efficacy of the biological therapies in cancer patients. In this prospective clinical trial we assessed in vivo effects of short term oral beta glucan administration on peripheral blood monocytes and their expression of activation markers in patients with advanced breast cancer. METHODS: 23 female patients with advanced breast cancer were included in the study. Median age of the patients was 52 years. Sixteen healthy females with a median age of 48 years served as the control group for comparing the initial blood samples. Peripheral blood samples were drawn on day zero and patients started receiving oral 1-3, 1-6, D-beta glucan daily. Blood samples were recollected on the 15th day. In the initial samples mean lymphocyte count was significantly lower in the patients with breast cancer (1281+/-306/mm(3) versus 1930+/-573/mm(3), p=0.04). In the patients with breast cancer, mean monocyte count which was 326+124/mm(3) at the beginning, was increased to 496+194/mm(3) at the 15th day (p=0.015). Expression of CD95 (Apo1/Fas) on CD14 positive monocytes was 48.17% at the beginning, which was increased to 69.23 % at the 15th day (p=0.002). Expression of CD45RA on CD14 positive monocytes was 49.9% at the beginning; it was increased significantly to 61.52% on day 15 (p=0.001). CONCLUSION: Oral beta glucan administration seems to stimulate proliferation and activation of peripheral blood monocytes in vivo in patients with advanced breast cancer. |
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Title:
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Dietary Flavonoid Intake and Breast Cancer Risk among Women on Long Island. |
| Author(s): |
Fink BN, Steck SE, Wolff MS, Britton JA, Kabat GC, Gaudet MM, Abrahamson PE,Bell P, Schroeder JC,Teitelbaum SL, Neugut AI, Gammon MD. |
| Flavonoids are found in a variety of foods and have anticarcinogenic properties in experimental models. Few epidemiologic studies have examined whether flavonoid intake is associated with breast cancer in humans. In this study, the authors investigated whether dietary flavonoid intake was associated with reduced risk of breast cancer in a population-based sample of US women. They conducted a case-control study among women who resided in Nassau and Suffolk counties on Long Island, New York. Cases and controls were interviewed about known and suspected risk factors and asked to complete a food frequency questionnaire regarding their average intake in the prior 12 months. A total of 1,434 breast cancer cases and 1,440 controls provided adequate responses. A decrease in breast cancer risk was associated with flavonoid intake; the decrease was most pronounced among postmenopausal women for flavonols (odds ratio (OR) = 0.54, 95% confidence interval (CI): 0.40, 0.73), flavones (OR = 0.61, 95% CI: 0.45, 0.83), flavan-3-ols (OR = 0.74, 95% CI: 0.55, 0.99), and lignans (OR = 0.69, 95% CI: 0.51, 0.94). The authors conclude that intake of flavonols, flavones, flavan-3-ols, and lignans is associated with reduced risk of incident postmenopausal breast cancer among Long Island women. These results suggest that US women can consume sufficient levels of flavonoids to benefit from their potential chemopreventive effects. |
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Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women's Intervention Nutrition Study. |
| Author(s): |
Chlebowski RT, Blackburn GL, Thomson CA, Nixon DW, Shapiro A, Hoy MK, Goodman MT, Giuliano AE, Karanja N, McAndrew P, Hudis C, Butler J, Merkel D, Kristal A,Caan B, Michaelson R, Vinciguerra V, Del Prete S, Winkler M, Hall R, Simon M,Winters BL, Elashoff |
| BACKGROUND: Preclinical and observational studies suggest a relationship between dietary fat intake and breast cancer, but the association remains controversial. We carried out a randomized, prospective, multicenter clinical trial to test the effect of a dietary intervention designed to reduce fat intake in women with resected, early-stage breast cancer receiving conventional cancer management. METHODS: A total of 2437 women were randomly assigned between February 1994 and January 2001 in a ratio of 40:60 to dietary intervention (n = 975) or control (n = 1462) groups. An interim analysis was performed after a median follow-up of 60 months when funding for the intervention ceased. Mean differences between dietary intervention and control groups in nutrient intakes and anthropometric variables were compared with t tests. Relapse-free survival was examined using Kaplan-Meier analysis, stratified log-rank tests, and Cox proportional hazards models. Statistical tests were two-sided. RESULTS: Dietary fat intake was lower in the intervention than in the control group (fat grams/day at 12 months, 33.3 [95% confidence interval {CI} = 32.2 to 34.5] versus 51.3 [95% CI = 50.0 to 52.7], respectively; P<.001), corresponding to a statistically significant (P = .005), 6-pound lower mean body weight in the intervention group. A total of 277 relapse events (local, regional, distant, or ipsilateral breast cancer recurrence or new contralateral breast cancer) have been reported in 96 of 975 (9.8%) women in the dietary group and 181 of 1462 (12.4%) women in the control group. The hazard ratio of relapse events in the intervention group compared with the control group was 0.76 (95% CI = 0.60 to 0.98, P = .077 for stratified log rank and P = .034 for adjusted Cox model analysis). Exploratory analyses suggested a differential effect of the dietary intervention based on hormonal receptor status. CONCLUSIONS: A lifestyle intervention reducing dietary fat intake, with modest influence on body weight, may improve relapse-free survival of breast cancer patients receiving conventional cancer management. Longer, ongoing nonintervention follow-up will address original protocol design plans, which called for 3 years of follow-up after completion of recruitment. |
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Title:
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Changes in emotion regulation and psychological adjustment following use of a group psychosocial support program for women recently diagnosed with breast cancer. |
| Author(s): |
Cameron LD, Booth RJ, Schlatter M, Ziginskas D, Harman JE. |
| This study assesses the efficacy of a group intervention in altering emotion regulation processes and promoting adjustment in women with breast cancer. Using a design with 10 alternating phases of availability of the intervention versus standard care, we assessed women participating in one of three conditions: a 12-week group intervention (N = 54); a decliner group who refused the intervention (N = 56), and a standard care group who were not offered the intervention (N = 44). The intervention included training in relaxation, guided imagery, meditation, emotional expression, and exercises promoting control beliefs and benefit-finding. Emotion regulation processes and adjustment were assessed at baseline (following diagnosis), 4 months (corresponding with the end of the intervention), 6 months, and 12 months. At 4 months, intervention participants (compared to decliners and standard care participants) reported greater increases in use of relaxation-oriented techniques, perceived control, emotional well-being, and coping efficacy, and, greater decreases in perceived risk of recurrence, cancer worry, and anxiety. Intervention participants also reported relatively greater decreases in emotional suppression from baseline to 12 months, suggesting that the intervention had a delayed impact on these tendencies. The findings suggest an emotion regulation intervention can beneficially influence emotional experiences and regulation over the first year following diagnosis. Copyright (c) 2006 John Wiley & Sons, Ltd. |
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Title:
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Dietary genistein reduces metastasis in a postsurgical orthotopic breast cancer model. |
| Author(s): |
Vantyghem SA, Wilson SM, Postenka CO, Al-Katib W, Tuck AB, Chambers AF. |
| Metastatic spread, not primary tumor burden, is the leading cause of breast cancer deaths. For patient prognosis to improve, new systemic adjuvant therapies that are capable of effectively inhibiting the outgrowth of seeded tumor cells after surgical treatment of the primary breast tumor are needed. To facilitate the preclinical development of such therapies, relevant animal models of breast cancer metastasis that can mimic the postsurgical adjuvant setting are required. Here we developed a preclinical xenograft model of breast cancer metastasis where the primary tumor was removed by surgical resection before systemic adjuvant treatment. We used this model to assess the antimetastatic effect of postsurgical dietary intervention with the soy isoflavone genistein. The anticancer activity of genistein has been established in vitro and in vivo, however, few studies have tested the potential of genistein as an antimetastatic therapy. Using our model, we tested the efficacy of adjuvant treatment with genistein to inhibit the outgrowth of metastases postsurgery. To establish primary tumors, human breast carcinoma cells, MDA-MB-435/HAL, were implanted into the mammary fat pad of female nude mice. Primary tumors were left to grow for 5 weeks before being surgically removed. Mice were then randomized into two diet groups: control soy-free diet versus genistein-supplemented diet. Five weeks later, metastatic burden was assessed. Genistein reduced the percent metastatic burden in the lungs by 10-fold. These results indicate that dietary intervention following cancer surgery can affect the outgrowth of seeded tumor cells. The availability of well-characterized, clinically relevant animal models for studying factors that regulate metastatic outgrowth postsurgery will provide an important tool for developing new systemic adjuvant therapies. |
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Title:
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Vitamin B6 suppresses growth of the feline mammary tumor cell line FRM. |
| Author(s): |
Shimada D, Fukuda A, Kanouchi H, Matsumoto M, Oka T. |
| Growth of FRM cells was inhibited by the addition of pyridoxine in a dose-dependent manner. Use of 5 mM pyridoxine caused an almost complete arrest of cell growth. Pyridoxal was as effective as pyridoxine, but pyridoxamine showed weak inhibitory action. Electron-microscopic examination of control cells revealed large nuclei and cellular membranes with villi, but, in pyridoxine-treated cells, condensed or degraded nuclei were observed. Many vacuoles and cholesterol crystals were widely distributed inside the cellular membrane of pyridoxine-treated cells. One of the vacuoles was identified as a lipid droplet. The DNA ladder was observed in the pyridoxine-treated cells. It is suggested that pyridoxine treatment of FRM cells causes cytolysis of cells by apoptosis. |
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Title:
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Use of complementary therapies among breast and prostate cancer patients during treatment: a multisite study. |
| Author(s): |
Hann D. M., Baker F., Roberts C. S., Witt C., McDonald J., Livingston M., Ruiterman J., Ampela R., Crammer C., Kaw O. |
| PURPOSE: The purpose of this study was to compare the use of complementary therapies (CT) among breast and prostate cancer patients during active cancer treatment. The authors compared use and beliefs about the role of CT in cancer recovery. METHODS: A self-report survey was completed by 126 breast cancer patients and 82 prostate cancer patients as part of a multisite research project. The self-report questionnaire inquired about the use of various CTs, sources of information about CT, reasons for using CT, beliefs about the benefits and risks of CT, demographic characteristics, and cancer treatment history. RESULTS: Most of the respondents were older than 50 years, Caucasian, married, had attended or completed college, and were less than 1 year postdiagnosis. Prostate cancer patients were significantly older than the breast cancer patients (P < .001). Several differences emerged between the groups. Compared to the prostate cancer patients, significantly more of the breast cancer patients reported using CT because they wanted to reduce the risk of recurrence (P < .01), play a more active role in recovery (P < .01), help manage stress (P < .01), take a more holistic approach (P < .01), or boost the immune system (P < .01). More of the prostate cancer patients reported using CT to have more control of their recovery (P < .05). The 2 groups also differed significantly (P < .01) on several beliefs about the potential benefits and risks of using CT. CONCLUSIONS: Most of the patients in this study had used some form of CT since the time of their diagnosis. Differences among breast and prostate cancer patients with regard to their use of CT during cancer treatment should be considered by oncology professionals who are discussing this topic with their patients. |
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Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer. |
| Author(s): |
Kuhl C.K., Schrading S., Leutner C.C., Morakkabati-Spitz N., Wardelmann E., Fimmers R., Kuhn W., Schild H.H. |
| PURPOSE: To compare the effectiveness of mammography, breast ultrasound, and magnetic resonance imaging (MRI) for surveillance of women at increased familial risk for breast cancer (lifetime risk of 20% or more). PATIENTS AND METHODS: We conducted a surveillance cohort study of 529 asymptomatic women who, based on their family history and/or mutational analysis, were suspected or proven to carry a breast cancer susceptibility gene (BRCA). A total of 1,542 annual surveillance rounds were completed with a mean follow-up of 5.3 years. Diagnostic accuracies of the three imaging modalities used alone or in different combinations were compared. RESULTS: Forty-three breast cancers were identified in the total cohort (34 invasive, nine ductal carcinoma-in-situ). Overall sensitivity of diagnostic imaging was 93% (40 of 43 breast cancers); overall node-positive rate was 16%, and one interval cancer occurred (one of 43 cancers, or 2%). In the analysis by modality, sensitivity was low for mammography (33%) and ultrasound (40%) or the combination of both (49%). MRI offered a significantly higher sensitivity (91%). The sensitivity of mammography in the higher risk groups was 25%, compared with 100% for MRI. Specificity of MRI (97.2%) was equivalent to that of mammography (96.8%). CONCLUSION: Mammography alone, and also mammography combined with breast ultrasound, seems insufficient for early diagnosis of breast cancer in women who are at increased familial risk with or without documented BRCA mutation. If MRI is used for surveillance, diagnosis of intraductal and invasive familial or hereditary cancer is achieved with a significantly higher sensitivity and at a more favorable stage. |
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Title:
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Exercise and lymphocyte activation following chemotherapy for breast cancer. |
| Author(s): |
Hutnick NA, Williams NI, Kraemer WJ, Orsega-Smith E, Dixon RH, Bleznak AD, Mastro AM. |
| PURPOSE: To determine whether exercise training would increase lymphocyte activation in patients with breast cancer following chemotherapy. Activation was determined by the presence of CD4(+)CD69(+) T-helper lymphocytes, mitogen-induced proliferation, and levels of cytokines produced by mitogen-stimulated lymphocytes and in the patients' plasma. METHODS: Patients with breast cancer (N = 28) who participated in a 6-month exercise program were compared with patients (N = 21) who did not exercise. Following chemotherapy, and 3 and 6 months later, patients underwent fitness evaluations and had blood drawn. The exercise program consisted of resistance training and aerobic activity at 60-75% functional capacity three times a week with a personal trainer. Immunochemistry and flow cytometry were used to measure the number of CD4(+)CD69(+) blood lymphocytes. Whole blood was stimulated with concanavalin A (ConA), phytohemagglutin (PHA), or pokeweed mitogen (PWM) to determine proliferation potential. Enzyme-linked immunosorbent assays (ELISA) were used to determine the concentration of interferon-gamma (IFN-gamma) and interleukin-6 (IL-6) in the culture medium of mitogen-stimulated lymphocytes as well as the plasma concentrations of IL-6, soluble IL-6 receptor, soluble gp130, and IFN-gamma. Analysis of groups across time was done using the Wilcoxon signed rank test, and comparisons of groups were done using the Mann-Whitney U test. RESULTS: The exercising patients showed increases in maximal oxygen uptake and upper body strength. This group also showed a greater percentage of CD4(+)CD69(+) cells and a greater level of tritiated thymidine incorporation (DNA synthesis) when stimulated with ConA, PHA, and PWM at the end of the intervention. Plasma and mitogen-stimulated IL-6 and IFN-gamma production were similar in both groups. CONCLUSION: Exercise may improve immune function by increasing lymphocyte activation in patients with breast cancer following treatment. |
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Title:
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Breast cancer and dietary factors in taiwanese women. |
| Author(s): |
Lee MM, Chang IY, Horng CF, Chang JS, Cheng SH, Huang A. |
| OBJECTIVES: To examine the effect of the consumption of dietary factors on the risk of breast cancer in a case-control study in Taiwan. METHODS: Two-hundred-and-fifty cases and 219 age-matched controls between the ages of 25 and 74 were interviewed in person between 1996 and 1999. Usual consumption of dietary habits including 100 foods was assessed using a food frequency questionnaire and a nutrient database developed and validated in Taiwanese populations. RESULTS: Cases consumed significantly more fat than controls. Cases also consumed statistically significant less supplements such as vitamins and mineral than controls. Food group analyses showed that highest quartile of beef and pork intake significantly increased risk in younger women (OR = 2.5, 95% CI = 1.0-6.0) and all women (OR = 2.5, 95% CI = 1.1-3.3). The age- education- and total calorie-adjusted odds ratio (OR) of breast cancer risk comparing the highest and second highest quartile of fat intake to the lowest quartile was 5.1, 95% confidence interval (CI): 2.1-13 and 3.5, 95% CI: 1.4-8.7 among those younger cases ( |
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Title:
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Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines. |
| Author(s): |
Ramachandran C, Rodriguez S, Ramachandran R, Raveendran Nair PK, Fonseca H, Khatib Z, Escalon E, Melnick SJ. |
| Curcumin (diferuloyl methane), the yellow-colored dietary pigment from the rhizomes of turmeric, has been recognized as a chemopreventive agent because of its antitumor, antioxidant and antiproliferative effects. The cytotoxic, apoptotic and gene regulatory effects of both turmeric and curcumin were investigated in the MCF-7 human breast cancer carcinoma cell line and compared with the effects in MCF-10A human mammary epithelial cells. MCF-7 cells were more sensitive to turmeric and curcumin than MCF-10A cells. MCF-10A cells retained comparatively less curcumin in the medium than MCF- 7 cells after 24 h, thereby reducing the cytotoxic effect. Curcumin induced a significantly higher percentage of apoptosis in MCF-7 than MCF-10A cells at all doses. Microarray hybridization of Clonetech apoptotic arrays with labeled first-strand probes of total RNA was performed to identify and characterize the genes regulated by curcumin in tumor cells. Of the 214 apoptosis-associated genes in the array, the expression of 104 genes was altered by curcumin treatment. The gene expression was altered up to 14-fold levels in MCF-7 as compared to only up to 1.5-fold in the MCF-10A cell line by curcumin. Curcumin up-regulated (>3 fold) 22 genes and down-regulated (<3-fold) 17 genes at both 25 microg/ml and 50 microg/ml doses in the MCF-7 cell line. The up-regulated genes include HIAP1, CRAF1, TRAF6, CASP1, CASP2, CASP3, CASP4, HPRT, GADD45, MCL-1, NIP1, BCL2L2, TRAP3, GSTP1, DAXX, PIG11, UBC, PIG3, PCNA, CDC10, JNK1 and RBP2. The down-regulated genes were TRAIL, TNFR, AP13, IGFBP3, SARP3, PKB, IGFBP, CASP7, CASP9, TNFSF6, TRICK2A, CAS, TRAIL-R2, RATS1, hTRIP, TNFb and TNFRSF5. While a dose-dependent gene expression change was noticed in some genes, opposite regulatory effects were induced by different curcumin doses in three apoptotic genes. These results suggest that curcumin induces apoptosis in breast cancer cells by regulation of multiple signaling pathways, indicating its potential use for prevention and treatment of cancer. |
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Title:
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Plasma carotenoids and recurrence-free survival in women with a history of breast cancer. |
| Author(s): |
Rock CL, Flatt SW, Natarajan L, Thomson CA, Bardwell WA, Newman VA, Hollenbach KA, Jones L, Caan BJ, Pierce JP. |
| PURPOSE: Previous studies suggest that diet may affect recurrence or survival rates in women who have been diagnosed with breast cancer. The purpose of this study was to examine the relationship between plasma carotenoid concentration, as a biomarker of vegetable and fruit intake, and risk for a new breast cancer event in a cohort of women with a history of early-stage breast cancer. METHODS: Participants were 1,551 women previously treated for breast cancer who were randomly assigned to the control arm of a diet intervention trial between March 1995 and November 2000. Outcome events were probed during semiannual interviews and verified by medical record review. During the period under study, 205 women had a recurrence or new primary breast cancer. Plasma carotenoid concentrations were measured in baseline blood samples. Hazard ratios (HR) and 95% CIs by quartiles of plasma carotenoids were computed, controlling for tumor stage, grade, and hormone receptor status; chemotherapy and tamoxifen therapy; clinical site; age at diagnosis; body mass index; and plasma cholesterol concentration. RESULTS: Women in the highest quartile of plasma total carotenoid concentration had significantly reduced risk for a new breast cancer event (HR, 0.57; 95% CI, 0.37 to 0.89), controlled for covariates influencing breast cancer prognosis. CONCLUSION: Plasma carotenoids are a biologic marker of intake of vegetables and fruit, so this observation supports findings from previous studies that have linked increased vegetable and fruit intake with greater likelihood of recurrence-free survival in women who have been diagnosed with early-stage breast cancer. |
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Title:
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Effects of exercise training on antitumor efficacy of doxorubicin in MDA-MB-231 breast cancer xenografts. |
| Author(s): |
Jones LW, Eves ND, Courneya KS, Chiu BK, Baracos VE, Hanson J, Johnson L, Mackey JR. |
| PURPOSE: Exercise is becoming readily accepted as a beneficial adjunct therapy to maintain or enhance quality of life in breast cancer patients undergoing adjuvant chemotherapy. An essential precursor to these studies is to investigate whether exercise modulates the antitumor efficacy of chemotherapeutic agents. EXPERIMENTAL DESIGN: Athymic female mice were transplanted with MDA-MB-231 breast xenografts and randomly assigned to one of four groups (n = 21 per group): (a) control, (b) exercise-only, (c) doxorubicin-only, or (d) exercise + doxorubicin. Exercise groups performed progressive treadmill running up to 18 m/min at 0% grade for 45 minutes, 5 d/wk for 8 weeks. RESULTS: Tumor growth delay was significantly longer in the doxorubicin-only and exercise + doxorubicin groups compared with the control (median 42 versus 25 days, P = 0.0082; 36 versus 25 days, P = 0.029, respectively) and exercise-only groups (median 42 versus 25 days, P = 0.029; 36 versus 25 days, P = 0.080, respectively). There was no significant difference between the doxorubicin-only and exercise + doxorubicin groups (median 42 versus 36 days, P = 0.33), suggesting that moderate intensity exercise does not significantly influence doxorubicin-induced tumor growth delay. CONCLUSION: These studies are essential to fully understand the safety and application of exercise as a supportive intervention in cancer control. |
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Title:
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Long-term weight change and breast cancer risk: the European prospective investigation into cancer and nutrition (EPIC). |
| Author(s): |
Lahmann PH, Schulz M, Hoffmann K, Boeing H, Tjonneland A, Olsen A, Overvad K, Key TJ, Allen NE, Khaw KT, Bingham S, Berglund G, Wirfalt E, Berrino F, Krogh V, Trichopoulou A, Lagiou P, Trichopoulos D, Kaaks R, Riboli E. |
| We examined prospectively the association between weight change during adulthood and breast cancer risk, using data on 1358 incident cases that developed during 5.8 years of follow-up among 40,429 premenopausal and 57,923 postmenopausal women from six European countries, taking part in the European prospective investigation into cancer and nutrition study. Multivariate Cox regression models were used to calculate hazard ratios according to weight change (kg), defined as the weight difference between age at enrollment and age 20 adjusted for other risk factors. Changes in weight were not associated with premenopausal breast cancer risk. In postmenopausal women, weight gain was positively associated with breast cancer risk only among noncurrent hormone replacement therapy (HRT) users (P-trend < or = 0.0002). Compared to women with a stable weight (+/-2 kg), the relative risk for women who gained 15-20 kg was 1.50 (95% confidence interval (CI) 1.06-2.13). The pooled RR per weight gain increment of 5 kg was 1.08 (95% CI 1.04-1.12). Weight gain was not associated with breast cancer risk in current HRT users, although, overall, these women experienced a much higher risk of breast cancer compared with nonusers. Our findings suggest that large adult weight gain was a significant predictor of breast cancer in postmenopausal women not taking exogenous hormones. |
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Title:
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Increase of survival benefit in advanced resectable colon cancer by extent of adjuvant treatment: results of a randomized trial comparing modulation of 5-FU + levamisole with folinic acid or with interferon-alpha. |
| Author(s): |
Link KH, Kornmann M, Staib L, Redenbacher M, Kron M, Beger HG; Study Group Oncology of Gastrointestinal Tumors. |
| BACKGROUND: The benefit of adjuvant therapy in curatively resected lymph node-positive colon cancer was established using 5-fluorouracil (5-FU) and levamisole (LEV) for 12 months. 5-FU cytotoxicity can be modulated by folinic acid (FA) or interferon-alpha (INF-alpha). The aim of this study was to investigate the efficacy of modulating 5-FU+ LEV by either FA or IFN-alpha in the adjuvant treatment of high-risk colon cancer. METHODS: Patients with curatively resected colon cancer (stages UICC IIb and III) were stratified according to T, N, and participating center and randomized to receive a 12-month treatment using 5-FU + LEV alone or in combination with FA or IFN-alpha. RESULTS: A total of 855 of 904 entered patients (94.6%) were eligible. The median follow-up of all eligible patients was 4.6 years. Addition of FA to 5-FU + LEV improved recurrence-free and overall survival in comparison with 5-FU + LEV alone (P = 0.007 and P = 0.004, respectively, 1-sided). The 5-year overall survival rates were 60.5% (95% confidence interval, 54.3-66.7) and 72.0% (95% confidence interval, 66.5-77.5) for 5-FU + LEV and 5-FU + LEV + FA, respectively. Addition of INF-alpha showed a tendency to improve recurrence-free survival, however, without altering overall survival. Toxicities (WHO III + IV) were generally tolerable except one toxic death in the control arm and were observed in 9.9% of the patients receiving 5-FU + LEV alone and in 13.3% and in 30.7% of patients receiving additional FA and IFN-alpha, respectively. CONCLUSIONS: Addition of IFN-alpha was associated with increased toxicity without markedly influencing the outcome and should therefore not be recommended for adjuvant treatment. Addition of FA increased the 5-year recurrence-free and overall survival rate by 9.3 and 11.5 percentage points, respectively. 5-FU + LEV + FA for 12 months may be an effective adjuvant treatment option for locally advanced high-risk colon cancer. |
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Title:
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Styrene and ethylene glycol have a synergetic effect on lipid peroxidation that is better protected than repaired by CoQ10. |
| Author(s): |
Dlugosz A, Sawicka E, Marchewka Z. |
| Previous study of a group of 22 workers occupationally exposed to styrene, ethylene glycol and their mixture at a paint and lacquer industry indicated significantly elevated concentration of malondialdehyde with 4-hydroxynonenal (MDA+4-HNE) in the blood plasma, successfully decreased with coenzyme Q10 (CoQ10) supplementation. The aim of present study is to evaluate whether the exposure to styrene or/and ethylene glycol could be responsible for the increase in MDA level. The mechanism of a single solvent action and the mixture was examined, specially whether it is connected with hydroxyl radical (*OH) generation. It was also investigated whether coenzyme Q10 could be considered as a protective (given before the solvents) or repairing (given after the solvents) agent in oxidative stress caused by the solvents. The results indicate that ethylene glycol nor styrene increase MDA and *OH, but as a mixture give synergetic interaction, elevating MDA and *OH concentration to a statistically significant extent. Coenzyme Q10 at a dose of 3.0 microg/ml only protects, but does not repair increased lipid peroxidation caused by ethylene glycol with styrene. In order to obtain both a protective and repairing effect, a concentration of 12.0 microg/ml CoQ is needed. |
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Title:
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Differential Anti-tumor Activity of Coriolus versicolor (Yunzhi) Extract through p53- and/or Bcl-2-Dependent Apoptotic Pathway in Human Breast Cancer Cells. |
| Author(s): |
Ho CY, Kim CF, Leung KN, Fung KP, Tse TF, Chan H, Lau CB. |
| Coriolus versicolor (CV), also called Yunzhi, has been demonstrated to exert anti-tumor effects on various types of cancer cells, but the underlying mechanism has not been fully elucidated. The present study aimed to evaluate the in vitro anti-tumor activity of a standardized aqueous ethanol extract prepared from CV on four breast cancer cell lines using MTT assay, and test whether the mechanism involves apoptosis induction and modulation of p53 and Bcl-2 protein expressions using cell death detection ELISA, p53 and Bcl-2 ELISAs respectively. Our results demonstrated that the CV extract dose-dependently suppressed the proliferation of three breast tumor cell lines, with ascending order of IC(50) values: T-47D, MCF-7, MDA-MB-231, while BT-20 cells were not significantly affected. Tumoricidal activity of the CV extract was found to be comparable to a chemotherapeutic anti-cancer drug, mitomycin C. Nucleosome productions in apoptotic MDA-MB-231, MCF-7 and T-47D cells were significantly augmented in a time-dependent manner and paralleled the anti-proliferative activity of CV extract. Expression of p53 protein was significantly upregulated only in T-47D cells treated with the CV extract in a dose- and time-dependent fashion, but not in MCF-7 (except at 400 mug/ml after 16 h) and MDA-MB-231 cells. The CV extract significantly induced a dose-dependent downregulation of Bcl-2 protein expression in MCF-7 and T-47D cells, but not in MDA-MB-231 cells. These results suggested that apoptosis induction, differentially dependent of p53 and Bcl-2 expressions, might be the possible mechanism of CV extract-mediated cytotoxicity in human breast cancer cells in vitro. |
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Title:
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Diet and biomarkers of oxidative damage in women previously treated for breast cancer. |
| Author(s): |
Thomson CA, Giuliano AR, Shaw JW, Rock CL, Ritenbaugh CK, Hakim IA, Hollenbach KA, Alberts DS, Pierce JP. |
| This study sought to evaluate the relationship between dietary intake of fat, polyunsaturated fat, saturated fat, arachidonic acid, and selected dietary antioxidants and levels of oxidative damage as measured by urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-epi-prostaglandin F2alpha (8-iso-PGF2alpha) in women previously treated for breast cancer. Two hundred two study subjects participating in the Women's Healthy Eating and Living (WHEL) study were included in this ancillary study. Dietary intakes and concentrations of urinary 8-OHdG and 8-iso-PGF2alpha were measured at baseline and 12 mo in the 179 women included in the analytical cohort. Study subjects demonstrated a significant reduction in dietary total, polyunsaturated, and saturated fat intake and a significant increase in vitamins E and C and beta-carotene intake from baseline to 12 mo. Linear mixed-models analysis using baseline and Year 1 data indicated that vitamin E intake was inversely associated with both 8-OHdG and 8-iso-PGF2alpha. 8-Iso-PGF2alpha is increased with increased body mass index (BMI) and polyunsaturated fatty acid (PUFA) intake, indicating an increase in lipid peroxidation with greater BMI and higher PUFA intake. 8-OHdG was inversely related to age but positively related to arachidonic acid, indicating an increase in DNA damage with higher intake of arachidonic acid (meat). The results of this nested case-controlled study provide potential mechanisms by which a high fruit and vegetable, low-fat diet might reduce the recurrence rate of or early-stage breast cancer. |
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Title:
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Physical activity and survival after breast cancer diagnosis. |
| Author(s): |
Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA. |
| CONTEXT: Physical activity has been shown to decrease the incidence of breast cancer, but the effect on recurrence or survival after a breast cancer diagnosis is not known. OBJECTIVE: To determine whether physical activity among women with breast cancer decreases their risk of death from breast cancer compared with more sedentary women. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study based on responses from 2987 female registered nurses in the Nurses' Health Study who were diagnosed with stage I, II, or III breast cancer between 1984 and 1998 and who were followed up until death or June 2002, whichever came first. MAIN OUTCOME MEASURE: Breast cancer mortality risk according to physical activity category (<3, 3-8.9, 9-14.9, 15-23.9, or > or =24 metabolic equivalent task [MET] hours per week). RESULTS: Compared with women who engaged in less than 3 MET-hours per week of physical activity, the adjusted relative risk (RR) of death from breast cancer was 0.80 (95% confidence interval [CI], 0.60-1.06) for 3 to 8.9 MET-hours per week; 0.50 (95% CI, 0.31-0.82) for 9 to 14.9 MET-hours per week; 0.56 (95% CI, 0.38-0.84) for 15 to 23.9 MET-hours per week; and 0.60 (95% CI, 0.40-0.89) for 24 or more MET-hours per week (P for trend = .004). Three MET-hours is equivalent to walking at average pace of 2 to 2.9 mph for 1 hour. The benefit of physical activity was particularly apparent among women with hormone-responsive tumors. The RR of breast cancer death for women with hormone-responsive tumors who engaged in 9 or more MET-hours per week of activity compared with women with hormone-responsive tumors who engaged in less than 9 MET-hours per week was 0.50 (95% CI, 0.34-0.74). Compared with women who engaged in less than 3 MET-hours per week of activity, the absolute unadjusted mortality risk reduction was 6% at 10 years for women who engaged in 9 or more MET-hours per week. CONCLUSIONS: Physical activity after a breast cancer diagnosis may reduce the risk of death from this disease. The greatest benefit occurred in women who performed the equivalent of walking 3 to 5 hours per week at an average pace, with little evidence of a correlation between increased benefit and greater energy expenditure. Women with breast cancer who follow US physical activity recommendations may improve their survival. |
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Title:
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Past recreational physical activity and risk of breast cancer. |
| Author(s): |
Macera CA. |
| OBJECTIVE: To examine the association between baseline and earlier recreational physical activity and incidence of breast cancer in postmenopausal women. DESIGN: Multicenter cohort study. SETTING: Women were enrolled in the Women's Health Initiative Observational Study (WHIOS) at 40 clinical centers between October 1993 and December 1998. PARTICIPANTS: Of a total of 93676 women enrolled in the WHIOS, 74171 were included in this analysis. Eligibility criteria were: aged 50 to 79 years, postmenopausal, and free of serious health conditions that might reduce survival during the following 3 years. Women were excluded if they reported a history of breast cancer or had missing physical activity data. Women of non-European extraction made up 15% of the sample. By February 28, 2002, 3.2% were lost to follow-up and 2.7% had died. ASSESSMENT OF RISK FACTORS: Participants completed baseline questionnaires that included information on medical and reproductive history, and health behaviors including physical activity and diet. Staff collected anthropometric data and information on use of hormone therapy. Women were asked if they usually exercised enough to work up a sweat > or =3 times per week at ages 18, 35, and 50 years. Current (baseline) walking for > or =10 minutes and participation in leisure-time activities were categorized by frequency, duration, and intensity. A current total activity variable was computed from the product of metabolic equivalent values and duration (MET h/wk). MAIN OUTCOME MEASURES: The main outcome measure was the association of incident breast cancer with measures of physical activity during a mean period of follow-up of 4.7 years. Cases of breast cancer were ascertained by the methods of the National Cancer Institute Surveillance, Epidemiology, and End Results guidelines, and collated by physicians and cancer coders blinded to exposure data. MAIN RESULTS: During follow-up, 1780 incident cases of breast cancer were documented. Women who had engaged in strenuous physical activity > or =3 times per week at age 35 had a decreased risk of breast cancer (multivariate adjusted relative risk [RR], 0.86; 95% CI, 0.78-0.95) compared with women who had not. The association was not significant for strenuous activity at age 50 or age 18 years. A greater amount of total current (baseline) physical activity was associated with a lower risk of breast cancer (P for trend, 0.03). Compared with no current physical activity, risk was reduced 18%, 11%, 17%, and 22% for women who exercised 5.1-10, 10.1-20, 20.1-40, and >40 MET h/wk. Hours of current moderate or strenuous physical activity was not significantly related to risk of breast cancer (P for trend, 0.12), although the highest duration category, >7 h/wk, compared with 0 h/wk showed a significant reduction in risk (RR, 0.79; CI, 0.63-0.99). When the women were divided by tertiles of body mass index (BMI cut points at 24.13 and 28.44 kg/m), increased total current activity was protective against breast cancer for those in the lowest tertile of BMI (P for trend, 0.03) but not for those in the upper tertiles (P for trend, 0.74 and 0.30). CONCLUSIONS: More physical activity was associated with a lower risk of breast cancer in postmenopausal American women. An hour every day of moderate or strenuous activity provided most benefit. |
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Title:
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Conjugated linoleic acid reduction of murine mammary tumor cell growth through 5-hydroxyeicosatetraenoic acid. |
| Author(s): |
Kim JH, Hubbard NE, Ziboh V, Erickson KL. |
| Conjugated linoleic acid (CLA) is a dietary fatty acid that has been shown to reduce tumorigenesis and metastasis in breast, prostate and colon cancer in animals. However, the mechanism of its action has not been clarified. The goal of this study was to determine whether CLA altered mouse mammary tumor cell growth and whether specific metabolites of the lipoxygenase pathway were involved in CLA action. Both t10, c12-CLA and a lipoxygenase inhibitor, but not c9, t11-CLA or linoleic acid (LA), reduced mouse mammary tumor cell viability and growth by inducing apoptosis and reducing cell proliferation. t10, c12-CLA reduced the production of the 5-lipoxygenase metabolite, 5-hydroxyeicosatetraenoic acid (5-HETE). That effect was not seen with c9, t11-CLA or LA. Adding 5-HETE back to tumor cells reduced the t10, c12-CLA effect on both apoptosis and cell proliferation. These data suggest that t10, c12-CLA reduction of tumor cell growth may involve the suppression of the 5-lipoxygenase metabolite, 5-HETE, with subsequent effects on apoptosis and cell proliferation. |
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Title:
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Food and botanical groupings and risk of breast cancer: a case-control study in Shanghai, China. |
| Author(s): |
Shannon J, Ray R, Wu C, Nelson Z, Gao DL, Li W, Hu W, Lampe J, Horner N, Satia J, Patterson R, Fitzgibbons D, Porter P, Thomas D. |
| Breast cancer incidence rates more than double in Chinese women as they migrate from China to Hong Kong to the United States, suggesting that environmental factors contribute to the international variation in breast cancer incidence. Several dietary factors, which differ between the United States and the Chinese population, including intake of soy, meat, and fruits and vegetables, have been suggested to affect breast cancer risk. This report describes results from a case-control study of diet and risk of breast cancer nested in a randomized trial of breast self exam in Shanghai, China. Participating breast cancer cases (n = 378) and frequency age-matched controls (n = 1,070) completed a comprehensive food frequency questionnaire and a risk factor questionnaire. After adjustment for age, total energy intake, and total years of breast-feeding, women in the highest quartile of fruit and vegetable intake (> or =3.8 servings/d) were significantly less likely to have breast cancer (odds ratio, 0.48; 95% confidence interval, 0.29-0.78) as compared with women in the lowest quartile of intake (< or =2.3 servings/d). Egg consumption was also significantly inversely associated with risk of breast cancer (odds ratio for > or =6.0 eggs/wk versus < or =2.0 eggs/wk is 0.56; 95% confidence interval, 0.35-0.91). There was no difference in soy consumption between cases and controls. None of the associations with a single botanical family explained the strong inverse relationship between fruits and vegetables and breast cancer risk. These results provide additional evidence in support of the important role of fruits and vegetables in breast cancer prevention. |
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Title:
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Ganoderma lucidum suppresses growth of breast cancer cells through the inhibition of Akt/NF-kappaB signaling. |
| Author(s): |
Jiang J, Slivova V, Harvey K, Valachovicova T, Sliva D. |
| Ganoderma lucidum (Reishi, Lingzhi) is a popular Asian mushroom that has been used for more than 2 millennia for the general promotion of health and was therefore called the "Mushroom of Immortality." Ganoderma lucidum was also used in traditional Chinese medicine to prevent or treat a variety of diseases, including cancer. We previously demonstrated that Ganoderma lucidum suppresses the invasive behavior of breast cancer cells by inhibiting the transcription factor NF-kappaB. However, the molecular mechanisms responsible for the inhibitory effects of Ganoderma lucidum on the growth of highly invasive and metastatic breast cancer cells has not been fully elucidated. Here, we show that Ganoderma lucidum inhibits proliferation of breast cancer MDA-MB-231 cells by downregulating Akt/NF-kappaB signaling. Ganoderma lucidum suppresses phosphorylation of Akt on Ser473 and downregulates the expression of Akt, which results in the inhibition of NF-kappaB activity in MDA-MB-231 cells. The biological effect of Ganoderma lucidum was demonstrated by cell cycle arrest at G0/G1, which was the result of the downregulation of expression of NF-kappaB-regulated cyclin D1, followed by the inhibition of cdk4. Our results suggest that Ganoderma lucidum inhibits the growth of MDA-MB-231 breast cancer cells by modulating Akt/NF-kappaB signaling and could have potential therapeutic use for the treatment of breast cancer. |
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Title:
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Evaluation of cell death caused by triterpene glycosides and phenolic substances from Cimicifuga racemosa extract in human MCF-7 breast cancer cells. |
| Author(s): |
Hostanska K, Nisslein T, Freudenstein J, Reichling J, Saller R. |
| We previously reported that the antiproliferative effect of an isopropanolic-aqueous extract of black cohosh (iCR) on MCF-7 estrogen-responsive breast cancer cell line was due to the induction of apoptosis. Here we address the question to what extent apoptosis induction can be ascribed to one of the two major fractions of iCR, the triterpene glycosides (TTG) or the cinnamic acid esters (CAE). Furthermore, as black cohosh is routinely administered orally, we studied whether its pharmacological effects would withstand simulated liver metabolism. The antiproliferative activity of TTG and CAE as well as of rat liver microsomal S9 fraction-pretreated iCR on MCF-7 cells were investigated by WST-1 assay. The features of cell death induced were tested for apoptosis by flow cytometry (light scatter characteristics, Annexin V binding). Irrespective of S9-pretreatment, 72 h iCR treatment induced a dose-dependent down regulation of cell proliferation with the same IC50 of 55.3 microg/ml dry residue which corresponds to 19.3 microg/ml TTG and 2.7 microg/ml CAE. The degree of apoptotic MCF-7 cells was also comparable. Both, isolated TTG and CAE fractions inhibited cell growth, the IC50 being 59.3 microg/ml and 26.1 microg/ml, respectively. Interestingly, whereas IC50 and apoptosis induction correspond well for the whole extract, TTG and CAE fractions induced apoptosis at concentrations (25 and 5 microg/ml) well below those required for significant growth inhibition. Observation of this study firstly showed that the cell death induced by iCR withstood a metabolic activation system. In addition, TTG and CAE compounds significantly contributed to its apoptotic effect, CAE being the more potent inhibitor of proliferation and apoptosis inducer. |
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Title:
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Chemoprevention by grape seed extract and genistein in carcinogen-induced mammary cancer in rats is diet dependent. |
| Author(s): |
Kim H, Hall P, Smith M, Kirk M, Prasain JK, Barnes S, Grubbs C. |
| Many popular dietary supplements are enriched in polyphenols such as the soy isoflavones, tea catechins, and resveratrol (from grape skins), each of which has been shown to have chemopreventive activity in cellular models of cancer. The proanthocyanidins, which are oligomers of the catechins, are enriched in grape seeds and form the basis of the dietary supplement grape seed extract (GSE). Evidence suggests that the proanthocyanidins may be metabolized to the monomeric catechins. This study was carried out to determine whether GSE added to rodent diets protected against carcinogen-induced mammary tumorigenesis in rats and whether this was affected by the composition of the whole diet. Female rats were begun on 5%, 1.25%, or 0% (control) GSE-supplemented diets at age 35 d. At age 50 d they were administered 7,12-dimethylbenz[a]anthracene (DMBA) in sesame oil at 80 mg/kg body weight. They were weighed and monitored weekly for tumor development until 120 d after DMBA administration. Administration of GSE in AIN-76A diet did not show any protective activity of GSE against DMBA-induced breast cancer. However, administration of GSE in a laboratory dry food diet (Teklad 4% rodent diet) resulted in a 50% reduction in tumor multiplicity. In similar experiments, genistein administered in AIN-76A diet also failed to show chemopreventive activity against the carcinogen N-methyl-N-nitrosourea; however, when administered at the same dose in the Teklad 4% rodent diet, genistein exhibited significant chemopreventive activity (44-61%). These results demonstrate that GSE is chemopreventive in an animal model of breast cancer; moreover, the diet dependency of the chemopreventive activity for both GSE and genistein suggests that whether or not a compound is chemopreventive may depend on the diet in which the agent is administered. |
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Title:
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Soy isoflavones suppress invasiveness of breast cancer cells by the inhibition of NF-kappaB/AP-1-dependent and -independent pathways. |
| Author(s): |
Valachovicova T, Slivova V, Bergman H, Shuherk J, Sliva D. |
| High consumption of soy products in some Asian countries has been linked to the low incidence of breast cancer in women. The chemopreventive effect of the soy isoflavone, genistein, has been observed through the suppression of cell proliferation, inhibition of angiogenesis and stimulation of apoptosis in breast carcinoma cells. Cancer metastasis consists of interdependent processes, including cell adhesion, migration and invasion. In the present study, we compare the effect of soy isoflavones in the form of aglycones (genistein, daidzein and glycitein) and glucosides (genistin, daidzin and glycitin) on the behavior of highly invasive breast cancer cells. Here we demonstrate that genistein suppresses cell adhesion and migration by inhibiting the constitutively active transcription factors NF-kappaB and AP-1, resulting in the suppression of secretion of urokinase-type plasminogen activator (uPA) in breast cancer cells MDA-MB-231. In addition, we show that all tested soy isoflavone aglycones (genistein, daidzein, glycitein) and glucosides (genistin, daidzin, glycitin) markedly reduced motility of MDA-MB-231 cells. However, only genistein and daidzein inhibited constitutively active NF-kappaB and AP-1 and suppressed secretion of uPA from breast cancer cells. Taken together, our results suggest that dietary soy isoflavones inhibit adhesion and motility of highly invasive breast cancer cells by distinct signaling pathways. |
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Title:
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Exercise manages fatigue during breast cancer treatment: A randomized controlled trial. |
| Author(s): |
Mock V, Frangakis C, Davidson NE, Ropka ME, Pickett M, Poniatowski B, Stewart KJ, Cameron L, Zawacki K, Podewils LJ, Cohen G, McCorkle R. |
| Fatigue is the most prevalent and debilitating symptom experienced by breast cancer patients receiving adjuvant chemotherapy or radiation therapy and few evidence-based treatments are available to manage this distressing side-effect. The purpose of this multi-institutional randomized controlled trial was to determine the effects of exercise on fatigue levels during treatment for breast cancer. Sedentary women (N=119) with Stage 0-III breast cancer receiving outpatient adjuvant chemotherapy or radiation therapy were randomized to a home-based moderate-intensity walking exercise program or to usual care for the duration of their cancer treatment. Of participants randomized to exercise, 72% adhered to the exercise prescription; 61% of the usual care group adhered. The intention-to-treat analysis revealed no group differences in part because of a dilution of treatment effect as 39% of the usual care group exercised and 28% of the exercise group did not. When exercise participation was considered using the data analysis method of instrumental variables with principal stratification, a clinically important and statistically significant (p=0.03) effect of exercise on pretest-to-posttest change in fatigue levels was demonstrated. Adherence to a home-based moderate-intensity walking exercise program may effectively mitigate the high levels of fatigue prevalent during cancer treatment. Copyright (c) 2004 John Wiley & Sons, Ltd. |
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Title:
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Assessing breast cancer risk: genetic factors are not the whole story. |
| Author(s): |
Korde LA, Calzone KA, Zujewski J. |
| Genetic syndromes that convey a significant risk of breast cancer are responsible for a small but significant percentage of these cancers. However, the vast majority of breast cancers occur in women with no family history of the disease. Nongenetic risk factors include age, previous breast disease, breast tissue density, radiation exposure, and lifestyle factors, such as weight, exercise, and alcohol consumption. In this article, the authors outline genetic and other risk factors for breast cancer, explore risk-reduction strategies, and encourage primary care physicians to assess breast cancer risk in all their patients. |
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Title:
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Sulforaphane inhibits human MCF-7 mammary cancer cell mitotic progression and tubulin polymerization. |
| Author(s): |
Jackson SJ, Singletary KW. |
| Sulforaphane (SUL), an isothiocyanate derived from hydrolysis of glucoraphanin in broccoli and other cruciferous vegetables, was shown to induce phase II detoxification enzymes, inhibit chemically induced mammary tumors in rodents, and more recently, to induce cell cycle arrest and apoptosis in colon cancer cells. In the present study, we demonstrate that SUL also acts to inhibit proliferation of MCF-7 adenocarcinoma cells from the human breast. Treatment of synchronized MCF-7 cells with 15 micromol/L SUL resulted in significant (P < 0.05) G(2)/M cell cycle arrest (167% of control) and elevated cyclin B1 protein (175% of control) within 24 h. Moreover, 15 micromol/L SUL significantly (P < 0.05) induced phosphorylation of histone H1 (167% of control), blocked cells in early mitosis ( approximately 10-fold increase over control), and disrupted polymerization of mitotic microtubules in vivo. Subsequent exposure of purified bovine brain tubulin to relatively high doses of SUL significantly (P < 0.05) inhibited both tubulin polymerization rate (51% of control) and total tubulin polymerization (78% of control) in vitro. Additionally, polymerization of purified tubulin exposed to isothiocyanate-containing analogs of SUL was similarly inhibited. Taken together, these findings indicate that SUL has mammary cancer suppressive actions involving mitotic cell cycle arrest and suggest a mechanism linked to the disruption of normal tubulin polymerization and/or more subtle effects on microtubule dynamics. |
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Title:
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Genistein induces Ca2+ -mediated, calpain/caspase-12-dependent apoptosis in breast cancer cells. |
| Author(s): |
Sergeev IN. |
| Genistein, a soy-derived isoflavone, has been suggested for breast cancer prevention; however, use of soy products for this purpose remains controversial. Genistein has been reported to regulate growth of tumor cells, although the involved molecular mechanisms are not defined. Here we report that genistein induces apoptosis in breast cancer cells via activation of the Ca2+ -dependent proapoptotic proteases, mu-calpain, and caspase-12. The treatment of MCF-7 breast cancer cells with genistein induced a sustained increase in concentration of intracellular Ca2+ resulting from depletion of the endoplasmic reticulum Ca2+ stores. This increase in Ca2+ was associated with activation of mu-calpain and caspase-12, as evaluated with the calpain and caspase-12 substrates and antibodies to active (cleaved) forms of the enzymes. Selective inhibition of Ca2+ binding sites of mu-calpain, forced increase of the cytosolic Ca2+ buffering capacity, and caspase inhibition decreased apoptotic indices in the genistein-treated cells. Our results suggest that Ca2+ -dependent proteases are potential targets for genistein in breast cancer cells and that the cellular Ca2+ regulatory activity of genistein underlies its apoptotic mechanism. |
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Title:
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A pilot clinical study of short-term isoflavone supplements in breast cancer patients. |
| Author(s): |
Sartippour MR, Rao JY, Apple S, Wu D, Henning S, Wang H, Elashoff R, Rubio R, Heber D, Brooks MN. |
| Many laboratory-based studies have shown that soy can suppress breast cancer proliferation. However, given the recent controversy generated by animal experiments that soy may under certain conditions stimulate breast cancer growth, we decided to carry out a pilot clinical trial in order to elucidate any interaction(s) between short-term isoflavone supplement administration and breast cancer growth. After a core-needle biopsy established the diagnosis of breast cancer, 17 patients were administered soy isoflavone tablets for two weeks. This surgically based study provided the unique opportunity to make objective observations based on human breast cancer tissues and blood obtained prior to and after isoflavone supplement treatment in the same patient. Twenty-six historical control cases with similar characteristics to the experimental patients were selected for comparison. We observed that the apoptosis/mitosis ratios in isoflavone-treated cancer specimens were not significantly different from those of control untreated cancer specimens. Furthermore, there appeared to be a statistically nonsignificant trend towards cancer growth inhibition in the isoflavone treatment group, as manifested by higher apoptosis/mitosis ratios compared with those from the control untreated group. Ex vivo/in vitro assays using serum from breast cancer patients prior to and at the conclusion of soy treatment reveal no significant proliferative changes on both breast cancer cells and endothelial cells. We concluded that the effect of soy on breast cancer deserves further studies in larger clinical trials. |
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Title:
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Effect of exercise on serum androgens in postmenopausal women: a 12-month randomized clinical trial. |
| Author(s): |
McTiernan A, Tworoger SS, Rajan KB, Yasui Y, Sorenson B, Ulrich CM, Chubak J, Stanczyk FZ, Bowen D, Irwin ML, Rudolph RE, Potter JD, Schwartz RS. |
| Postmenopausal women with elevated circulating androgen concentrations have an increased risk of developing breast cancer, yet interventions to reduce androgen levels have not been identified. We examined the effects of a 12-month moderate intensity exercise intervention on serum androgens. The study was a randomized clinical trial in 173 sedentary, overweight (body mass index > or = 24.0 kg/m(2), body fat > 33%), postmenopausal women, ages 50 to 75 years, not using hormone therapy and living in the Seattle, WA area. The exercise intervention included facility-based and home-based exercise (45 minutes, 5 days per week of moderate intensity sports/recreational exercise). A total of 170 (98.3%) women completed the study, with exercisers averaging 171 minutes per week of exercise. Women in the exercise and control groups experienced similar, nonsignificant declines in most androgens. Among women who lost >2% body fat, testosterone and free testosterone concentrations fell by 10.1% and 12.2% between baseline and 12 months in exercisers compared with a decrease of 1.6% and 8.0% in controls (P = 0.02 and 0.03 compared with exercisers, respectively). Concentrations of testosterone and free testosterone among exercisers who lost between 0.5% and 2% body fat declined by 4.7% and 10.4%. In controls who lost this amount of body fat, concentrations of testosterone and free testosterone declined by only 2.8% and 4.3% (P = 0.03 and 0.01 compared with exercisers, respectively). In summary, given similar levels of body fat loss, women randomized to a 12-month exercise intervention had greater declines in testosterone and free testosterone compared with controls. The association between exercise and breast cancer risk may be partly explained by the effects of exercise on these hormones. |
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Title:
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Rh2, a compound extracted from ginseng, hypersensitizes multidrug-resistant tumor cells to chemotherapy. |
| Author(s): |
Jia WW, Bu X, Philips D, Yan H, Liu G, Chen X, Bush JA, Li G. |
| Rh2 is a ginsenoside extracted from ginseng that has drawn attention in a few laboratories in Asian countries because of its potential tumor-inhibitory effect. In the present study, we tested Rh2 on many tumor-cell lines for its effects on cell proliferation, induction of apoptosis, and potential interaction with conventional chemotherapy agents. Our results showed that Rh2 inhibited cell growth by G1 arrest at low concentrations and induced apoptosis at high concentrations in a variety of tumor-cell lines, possibly through activation of caspases. The growth arrest and apoptosis may be mediated by 2 separate mechanisms. Apoptosis is not dependent on expression of the wild-type p53 nor the caspase 3. In addition, the apoptosis induced by Rh2 was mediated through glucocorticoid receptors. Most interestingly, Rh2 can act either additively or synergistically with chemotherapy drugs on cancer cells. Particularly, it hypersensitized multidrug-resistant breast cancer cells to paclitaxel. These results suggest that Rh2 possesses strong tumor-inhibiting properties, and potentially can be used in treatments for multidrug-resistant cancers, especially when it is used in combination with conventional chemotherapy agents. |
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Title:
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Dietary phytoestrogen intake and premenopausal breast cancer risk in a German case-control study. |
| Author(s): |
Linseisen J, Piller R, Hermann S, Chang-Claude J; German Case-Control Study. |
| A diet high in isoflavonoids (soy) is associated with lower breast cancer risk in Asian populations. Due to the low soy intake, dietary lignans may be the more important phytoestrogen class in Western populations. We used a population-based case-control study of breast cancer by age 50 in southern Germany to evaluate the association between dietary intake of different phytoestrogens and premenopausal breast cancer risk. Dietary information was collected from 278 premenopausal cases and 666 age-matched controls, using a validated FFQ. Using multivariate logistic regression, the highest vs. lowest intake quartiles of daidzein and genistein yielded significantly reduced ORs (95% CI) for breast cancer risk of 0.62 (0.40-0.95) and 0.47 (0.29-0.74), respectively. The protective effects of daidzein and genistein were found only for hormone receptor-positive tumors. High intake of other isoflavonoids, e.g., formononetin and biochanin A, as well as the sum of isoflavonoids were not associated with a decrease in risk. Breast cancer risk significantly decreased with a high intake of the plant lignan matairesinol (OR = 0.58, 95% CI 0.37-0.94) but not secoisolariciresinol or the sum of plant lignans. However, both estimated mammalian lignans, enterodiol and enterolactone, were inversely associated with breast cancer risk, with ORs (95% CI) of 0.61 (0.39-0.98) and 0.57 (0.35-0.92), respectively. No effect was found for total phytoestrogen intake. Our results suggest an important role of dietary intake of daidzein and genistein, despite low levels, as well as of matairesinol and mammalian lignans to reduce premenopausal breast cancer risk in this study population. Copyright 2004 Wiley-Liss, Inc. |
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Title:
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Differential inhibition of fatty acid transport in tissue-isolated steroid receptor negative human breast cancer xenografts perfused in situ with isomers of conjugated linoleic acid. |
| Author(s): |
Dauchy RT, Dauchy EM, Sauer LA, Blask DE, Davidson LK, Krause JA, Lynch DT. |
| In established rodent tumors and human cancer cell lines, conjugated dienoic isomers of linoleic acid (CLA) suppress the growth-stimulating effects of linoleic acid (LA) and its metabolism to the mitogenic agent, 13-hydroxyoctadecadienoic acid (13-HODE). Here, we compared the effects of three CLA isomers on LA uptake and metabolism, and growth in human breast xenografts perfused in situ in female nude rats. The results demonstrated that two CLA isomers [10t, 12c-CLA>9t, 11t-CLA] caused a dose-dependent inhibition of LA uptake, cAMP content, 13-HODE formation, Erk 1/2 activity, and [(3)H]thymidine incorporation into tumor DNA; 9c, 11t-CLA showed no effect. The inhibitory effect is reversible with either pertussis toxin (PTX) or 8-Br-cAMP suggesting that CLA isomers differentially inhibit LA uptake and metabolism and cell proliferation in human breast cancer in vivo via a receptor-mediated, PTX-sensitive pathway. |
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Title:
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Concomitant administration of an isopropanolic extract of black cohosh and tamoxifen in the in vivo tumor model of implanted RUCA-I rat endometrial adenocarcinoma cells. |
| Author(s): |
Nisslein T, Freudenstein J. |
| Black cohosh is a well known herbal remedy of long traditional use against menopausal complaints. Recently published studies on postmenopausal hormone replacement with synthetic substances associated severe negative side effects with an increase in duration of administration. The subsequent popularity of alternative treatments, often herbal drugs, made investigations into the safety of these preparations more pressing. Until now, black cohosh demonstrated no estrogen-agonistic activity in mammary cells, neither in animal model nor in cell culture, i.e., no gene transcription or cell proliferation was induced. Here we tested for the influence of a standardized isopropanolic extract of black cohosh on an animal model of endometrial cancer. Ectopic growth of the primary tumor as well as the incidence and localization of metastases were examined, partly in the setting of a combination treatment with tamoxifen. In contrast to the endometrial estrogen agonist tamoxifen, black cohosh did not further growth or metastasizing potential of the primary tumor. Absence of detectable supportive or antagonistic effects between both treatments most probable come from the relatively high tamoxifen dose. |
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Title:
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Phyto-oestrogens and breast cancer chemoprevention. |
| Author(s): |
Limer JL, Speirs V. |
| Phytoestrogens are polyphenol compounds of plant origin that exhibit a structural similarity to the mammalian steroid hormone 17beta-oestradiol. In Asian nations the staple consumption of phyto-oestrogen-rich foodstuffs correlates with a reduced incidence of breast cancer. Human dietary intervention trials have noted a direct relationship between phyto-oestrogen ingestion and a favourable hormonal profile associated with decreased breast cancer risk. However, these studies failed to ascertain the precise effect of dietary phyto-oestrogens on the proliferation of mammary tissue. Epidemiological and rodent studies crucially suggest that breast cancer chemoprevention by dietary phyto-oestrogen compounds is dependent on ingestion before puberty, when the mammary gland is relatively immature. Phyto-oestrogen supplements are commercially marketed for use by postmenopausal women as natural and safe alternatives to hormone replacement therapy. Of current concern is the effect of phyto-oestrogen compounds on the growth of pre-existing breast tumours. Data are contradictory, with cell culture studies reporting both the oestrogenic stimulation of oestrogen receptor-positive breast cancer cell lines and the antagonism of tamoxifen activity at physiological phyto-oestrogen concentrations. Conversely, phyto-oestrogen ingestion by rodents is associated with the development of less aggressive breast tumours with reduced metastatic potential. Despite the present ambiguity, current data do suggest a potential benefit from use of phyto-oestrogens in breast cancer chemoprevention and therapy. These aspects are discussed. |
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Title:
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Highly sensitive detection of the MGB1 transcript (mammaglobin) in the peripheral blood of breast cancer patients. |
| Author(s): |
Cerveira N, Torres L, Rocha P, Bizarro S, Pereira D, Abreu J, Henrique R, Teixeira MR, Castedo S. |
| We describe a new one-step RT-PCR assay for the detection of the mammaglobin (MGB1) gene transcript in the peripheral blood of breast cancer patients. With this approach, the MGB1 transcript could be detected in the peripheral blood of 22 of 54 (41%) breast cancer patients prior to any therapy. This method, using specific primers for cDNA synthesis, proved to be more sensitive (10(-6) to 10(-11), usually 10(-7)) than previously reported methodologies. This increased sensitivity was achieved without compromising specificity, as the MGB1 transcript was not detected in 38 blood samples of healthy donors and in only 1 of 18 blood samples of patients presenting with hematologic malignancies. A positive correlation was seen between MGB1 positivity and breast cancer stage: 0/3 (0%) in stage 0, 3/13 (23%) in stage I, 6/17 (35%) in stage II, 5/10 (50%) in stage III, 8/11 (73%) in stage IV (p = 0.003). The prognostic and therapeutic implications of MGB1 positivity by one-step RT-PCR in the peripheral blood of breast cancer patients, especially in clinically localized disease (stages I and II), should be evaluated after long-term clinical follow-up of these patients. Copyright 2003 Wiley-Liss, Inc. |
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Title:
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Growth inhibitory activity of extracts and purified components of black cohosh on human breast cancer cells. |
| Author(s): |
Einbond LS, Shimizu M, Xiao D, Nuntanakorn P, Lim JT, Suzui M, Seter C, Pertel T, Kennelly EJ, Kronenberg F, Weinstein IB. |
| The purpose of this study was to determine whether black cohosh contains constituents that inhibit the growth of human breast cancer cells, and therefore might eventually be useful in the prevention or treatment of breast cancer. Black cohosh rhizomes were extracted with methanol/water and fractionated by solvent-solvent partitioning to yield three fractions: hexane, ethyl acetate and water. The ethyl acetate fraction displayed the highest potency in two cell-based assays, growth inhibition and cell cycle analysis. This fraction inhibited growth of both the ER(+) MCF7 and ER(-)MDA-MB-453 human breast cancer cell lines with IC(50) values of about 20 and 10 micro g/ml, respectively. It also induced cell cycle arrest at G1 when tested at 30 micro g/ml and at G2/M at 60 micro g/ml in MCF7 cells. This suggests that the extract contains a mixture of components with the more active (or more abundant) causing G1 arrest and the less active causing G2/M arrest. We then examined specific components in this extract. The triterpene glycoside fraction obtained by polyamide column chromatography, and the specific triterpene glycosides actein, 23-epi-26-deoxyactein and cimiracemoside A, inhibited growth of the MCF7 human breast cancer cells and induced cell cycle arrest at G1. The most potent compound, actein, decreased the level of cyclin D1, cdk4 and the hyperphosphorylated form of the pRb protein and increased the level of p21(cip1) in MCF7 cells, changes that may contribute to the arrest in G1. Further studies are in progress to identify the mechanisms by which actein and related compounds present in black cohosh inhibit growth of human breast cancer cells. |
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Title:
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Energy balance in early breast cancer patients receiving adjuvant chemotherapy. |
| Author(s): |
Harvie MN, Campbell IT, Baildam A, Howell A. |
| Weight gain is a common problem amongst women receiving adjuvant chemotherapy for early breast cancer. We undertook a study to determine the causes of this weight gain. Prospective measurements of body mass and composition (skinfolds, bioelectrical impedance, total body potassium), energy balance (resting energy expenditure dietary intake, and physical activity), were determined in 17 women during and in the 6 months after commencing adjuvant chemotherapy. Women gained significant amounts of weight (5.0 +/- 3.8; p < 0.01) and body fat (7.1 kg +/- 4.5; p < 0.01) over the year. Waist circumference (5.1 +/- 4.5 cm; p < 0.01) and abdominal skinfold (16.2 +/- 10 mm; p < 0.01) were also increased but there was a decline in fat free mass (FFM); 1.7 +/- 2.5 kg. Women due to receive adjuvant chemotherapy had a greater resting energy expenditure (REE) compared with healthy subjects ( n = 21); 100.5 +/- 8.0% Harris Benedict compared to 94.5 +/- 8.4% Harris Benedict ( p = 0.05). REE declined by 3% during adjuvant chemotherapy ( p < 0.05), and remained depressed until at least 3 months posttreatment. There were no significant changes in dietary intake or physical activity over the year. Failure of women to reduce their energy intake to compensate for the decreased energy requirement may account for some of the weight gain. Treatment of adjuvant chemotherapy causes gain of body fat because of reduced energy expenditure, and the failure of women to reduce their energy intake to compensate for the decline in energy requirement during and in the 6 months posttreatment. Since weight gain impacts on survival, patients should be counselled to reduce energy intake and exercise during and after adjuvant treatment. |
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Title:
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Isomers of conjugated linoleic Acid differ in their effects on angiogenesis and survival of mouse mammary adipose vasculature. |
| Author(s): |
Masso-Welch PA, Zangani D, Ip C, Vaughan MM, Shoemaker SF, McGee SO, Ip MM. |
| Dietary conjugated linoleic acid (CLA) is a cancer chemopreventive agent that has been shown to inhibit angiogenesis in vivo and in vitro, and to decrease vascular endothelial growth factor (VEGF) and Flk-1 concentrations in the mouse mammary gland. To determine which isomer mediates the antiangiogenic effects of CLA in vivo, the effects of diets supplemented with 5 or 10 g/kg c9,t11- or t10,c12-CLA isomers were compared in CD2F1Cr mice. Both isomers inhibited functional vascularization of a matrigel pellet in vivo and decreased serum VEGF concentrations; the t10,c12 isomer also decreased the proangiogenic hormone leptin (P < 0.05). Additionally, the t10,c12 isomer, but not c9,t11-CLA, rapidly induced apoptosis of the white and brown adipocytes as well as the preexisting supporting vasculature of the mammary fat pad (P < 0.05). Independent of this isomer-specific adipose apoptotic effect, both isomers induced a rapid and reversible decrease in the diameter of the unilocular adipocytes (P < 0.05). The ability of both CLA isomers to inhibit angiogenesis in vivo may contribute to their ability to inhibit carcinogenesis. Moreover, we propose that each CLA isomer uniquely modifies the mammary stromal "soil" in a manner that is useful for chemoprevention of breast cancer. |
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Title:
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Early identification of individuals with prostate cancer in negative biopsies. |
| Author(s): |
Dhir R, Vietmeier B, Arlotti J, Acquafondata M, Landsittel D, Masterson R, Getzenberg RH. |
| PURPOSE: The use of prostate specific antigen (PSA) to screen individuals for prostate cancer has changed the management of the disease, permitting early detection in men. Repeat biopsies for persistently increased PSA are not uncommon with prostate cancer never being detected in many of the men. The novel prostate cancer marker, EPCA, is expressed throughout the prostate of individuals with prostate cancer but not in those without the disease. MATERIALS AND METHODS: The expression of ECPA was studied to identify those men with initially negative biopsies who were ultimately found to have prostate cancer. Negative biopsies, subsequent biopsies and prostatectomy specimens were evaluated by quantitative immunohistochemistry. RESULTS: The EPCA staining intensity in the samples analyzed from the patient cohort with prostate carcinoma were significantly different compared to controls (p <0.001) with almost no overlap in staining results. Sensitivity of the EPCA immunohistochemistry is 84% and specificity is 85%. CONCLUSIONS: An immunohistochemical test for EPCA could serve as an adjunct to the current diagnostic approach to a patient who undergoes prostate needle biopsy, and could identify individuals with prostate cancer as much as 5 or more years earlier than the current diagnostic approach and algorithms. In addition, this test might also help limit the numbers of biopsies performed as part of subsequent routine evaluation for increased PSA. |
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Title:
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Complementary and alternative medicine use by women after completion of allopathic treatment for breast cancer. |
| Author(s): |
Henderson JW, Donatelle RJ. |
| CONTEXT: A growing number of women are being diagnosed and successfully treated for breast cancer. Therefore, many women are living with a history of breast cancer. The use of complementary and alternative therapies within this patient population has increased. OBJECTIVE: To determine post breast cancer treatment health behaviors with regard to use of complementary and alternative therapies. DESIGN: Survey participants were asked about their use of 15 complementary and alternative medicine (CAM) therapies. In order to determine the relative importance of the hypothesized predictor variables, standard logistic regression was performed with CAM use as the dependent variable. PARTICIPANTS: 551 women who had been diagnosed with breast cancer and were post treatment. INTERVENTION: Telephone Survey. RESULTS: Telephone interviews were conducted with 551 females in the Portland, Oregon, metropolitan area who had been diagnosed with breast cancer an average of 3.5 years earlier. Two-thirds (66%) of the women used at least one CAM therapy during the previous 12 months, and the majority of them perceived that their CAM use was without the recommendation of their doctor. Relaxation/meditation, herbs, spiritual healing, and megavitamins were used most often. Significant predictors of CAM use included younger age, higher education, and private insurance. The majority of the CAM therapies were perceived by their users to be at least "moderately important" in remaining free of cancer. The reasons given for using CAM were to enhance overall quality of life, to feel more in control, to strengthen the immune system, and to reduce stress. CONCLUSIONS: Two-thirds of women in this study followed conventional treatment for breast cancer with one or more CAM therapies, which, they believed, could prevent cancer recurrence and/or improve their quality of life. CAM use did not reflect negative attitudes towards conventional medical care, but rather an orientation to self-care in the optimization of their health and well being. |
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Title:
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Intakes of plant foods, fibre and fat and risk of breast cancer - a prospective study in the Malmo Diet and Cancer cohort. |
| Author(s): |
Mattisson I, Wirfalt E, Johansson U, Gullberg B, Olsson H, Berglund G. |
| The objective of this study was to investigate prospectively the associations between intakes of plant foods, fibre and relative fat and risk of breast cancer in a subsample of 11 726 postmenopausal women in the Malmo Diet and Cancer cohort. Data were obtained by an interview-based diet history method, a structured questionnaire, anthropometrical measurements and national and regional cancer registries. During 89 602 person-years of follow-up, 342 incident cases were documented. Cox regression analysis examined breast cancer risks adjusted for potential confounders. High fibre intakes were associated with a lower risk of postmenopausal breast cancer, incidence rate ratio=0.58, 95% CI: 0.40, 0.84, for the highest quintile of fibre intake compared to the lowest quintile. The combination high fibre-low fat had the lowest risk when examining the effect in each cell of cross-classified tertiles of fibre and fat intakes. An interaction (P=0.049) was found between fibre- and fat-tertiles. There was no significant association between breast cancer risk and intakes of any of the plant food subgroups. These findings support the hypothesis that a dietary pattern characterised by high fibre and low fat intakes is associated with a lower risk of postmenopausal breast cancer.British Journal of Cancer (2004) 90, 122-127. doi:10.1038/sj.bjc.6601516 www.bjcancer.com |
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Title:
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Combined inhibition of estrogen-dependent human breast carcinoma by soy and tea bioactive components in mice. |
| Author(s): |
Zhou JR, Yu L, Mai Z, Blackburn GL. |
| Breast cancer is significantly less prevalent among Asian women, whose diets contain high intake of soy products and tea. The objective of our present study was to identify the combined effects of dietary soy phytochemicals and tea components on breast tumor progression in a clinically relevant in vivo model of MCF-7 androgen-dependent human breast tumor in female SCID mice. MCF-7 tumor growth, tumor cell proliferation and apoptosis, microvessel density, and expressions of tumor estrogen receptors were compared in mice treated with genistin-rich soy isoflavones (GSI), soy phytochemical concentrate (SPC), black tea (BT), green tea (GT), SPC/BT combination and SPC/GT combination. GSI and SPC led to dose-dependent inhibition of MCF-7 tumor growth via inhibition of cancer cell proliferation in vivo. GT showed more potent anti-breast tumor activity than BT. GT infusion at 1.5 g tealeaf/100 mL water produced significant (p < 0.05) reductions of 56% in final tumor weight. GT plus SPC at 0.1% of the diet further reduced final tumor weight by 72% (p < 0.005). Analysis of serum and tumor biomarkers showed that the combined effects of SPC and GT inhibited tumor angiogenesis, and reduced estrogen receptor (ER)-alpha and serum levels of insulin-like growth factor (IGF)-I. Our study suggests that dietary SPC plus GT may be used as a potential effective dietary regimen for inhibiting progression of estrogen-dependent breast cancer. Copyright 2003 Wiley-Liss, Inc. |
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Title:
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Nutrition-related issues for the breast cancer survivor. |
| Author(s): |
Demark-Wahnefried W, Rock CL. |
| Nutritional status and dietary intake play a significant role in the prognosis of breast cancer patients and may modify the progression of disease, as well as influence risk for comorbid conditions, such as osteoporosis and cardiovascular disease. A critical review of relevant clinical and epidemiological studies identified through MEDLINE and CINAHL searches was undertaken to provide the clinician with a summary of evidence that could form the appropriate guidance of women diagnosed with breast cancer who seek to reduce their risk of progressive or recurrent disease, and improve their overall health. Currently, healthy weight control with an emphasis on exercise to preserve or increase both lean body and bone masses, and plant-based diets that include ample amounts of nutrient-dense, low-energy density foods, particularly vegetables, can be recommended. Furthermore, diets high in vegetables, fruit, whole grains, and low-fat dairy foods, and low in saturated fat, may help to lower overall disease risk in this population. |
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Title:
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Lifetime recreational exercise activity and risk of breast carcinoma in situ. |
| Author(s): |
Patel AV, Press MF, Meeske K, Calle EE, Bernstein L. |
| BACKGROUND: The incidence rates of breast carcinoma in situ (BCIS) have increased dramatically over the past two decades, primarily because of increased mammography screening. Ductal carcinoma in situ, which accounts for approximately 85% of BCIS and 10-20% of all breast carcinomas, is generally recognized as the final step in the progression to invasive disease. To the authors' knowledge, few studies have been conducted to date to evaluate BCIS risk factors. Because of its potential effects on circulating sex hormones, physical activity has been proposed as a modifiable risk factor for invasive breast carcinoma. However, the relation to BCIS risk is poorly understood. METHODS: The authors analyzed data from a population-based case-control study conducted in Los Angeles County. Personal interviews were conducted with 567 white and black women (age range, 35-64 years) who had been newly diagnosed with BCIS between March 1, 1995 and May 31, 1998 and with 1026 control subjects, of whom 616 were screened within 2 years of identification. RESULTS: After excluding unscreened control subjects (n = 410) and adjusting for potential confounding factors, the risk of BCIS was approximately 35% lower among women with any exercise activity compared with inactive women, although no significant trend was observed. The association between exercise activity and the risk of BCIS was modified by a family history of breast carcinoma. No reduction in risk was observed among women reporting a first-degree family history of breast carcinoma (homogeneity of trends P value = 0.02). CONCLUSIONS: The findings of the current study suggest that exercise activity may modify the risk of BCIS, particularly among women without a family history of breast carcinoma. Copyright 2003 American Cancer Society. |
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Title:
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Inositol hexaphosphate (IP6) inhibits key events of cancer metastasis: II. Effects on integrins and focal adhesions. |
| Author(s): |
Tantivejkul K, Vucenik I, Shamsuddin AM. |
| BACKGROUND: We have shown that inositol hexaphosphate (IP6), a natural compound and a potent anti-cancer agent, inhibited cancer cell adhesion to the extracellular matrix (ECM) proteins, thereby leading to inhibition of cell migration and invasion. Cell adhesion to ECM is mediated by specific cell surface integrins, which transduce intracellular signals through their interaction and activation of other proteins that are recruited to the focal adhesion. We hypothesize that IP6 decreases cell adhesion by suppressing the integrin receptors and their subsequent signaling pathway. MATERIALS AND METHODS: We analyzed integrin expressions of the highly invasive estrogen receptor-negative human breast cancer MDA-MB 231 cells exposed to IP6 by flow cytometry. The expression of focal adhesion proteins was investigated by immunocytochemistry and Western blotting. RESULTS: IP6 treatment caused a significant (P < 0.005) decrease in the expression of integrin heterodimers alpha 2 beta 1 (collagen receptor), alpha 5 beta 1 (fibronectin receptor) and alpha v beta 3 (vitronectin receptor); flow cytometry showed that it was the alpha 5 subunit that was down-regulated ( < 0.001). However, the expression of the alpha 2, alpha v, beta 1 and beta 3 subunits were not affected by IP6 treatment. When the expression of integrins on the cell surface was assessed, there was a dramatic 82% decrease in the expression of alpha 5 beta 1 on IP6-treated cells (P < 0.0001), indicating a decrease in cell surface expression of the heterodimers. No effect was seen when inositol hexasulfate (IS6), an analogue of IP6, was used as a control. Immunocytochemistry showed a lack of clustering of paxillin; tyrosine-phosphorylated proteins in IP6-treated cells were discontinuous and scattered around the cell periphery, whereas the patterns were more dense and localized in control cells. Consistent with these observations, focal adhesion kinase (FAK) autophosphorylation at tyrosine-397 residue was suppressed, albeit modestly, by IP6 treatment, suggesting a down-regulation in the integrin-mediated signaling pathway. CONCLUSION: The results of this study indicate that IP6-induced inhibition of cancer cell adhesion, migration and invasion may be mediated through the modulation of integrin dimerization, cell surface expression and integrin-associated signaling pathway. |
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Title:
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Dietary genistein results in larger MNU-induced, estrogen-dependent mammary tumors following ovariectomy of sprague-dawley rats. |
| Author(s): |
Allred CD, Allred KF, Ju YH, Clausen LM, Doerge DR, Schantz SL, Korol DL, Wallig MA, Helferich WG. |
| Due to the estrogenic properties of soy derived isoflavones, many postmenopausal women are using these compounds as a natural alternative to hormone replacement therapy (HRT). How isoflavones impact breast cancer in postmenopausal women is important, because a majority of breast cancer cases occur in this age group. Chemical induction of mammary tumors in female rats has been used to determine that exposure of the mammary gland to soy isoflavones prior to tumor induction is protective against tumor formation. Here we investigate the effect of dietary genistein on mammary tumors that have already formed. The study was designed to determine the action of dietary genistein in a low endogenous estrogen environment as is observed in postmenopausal women. Animals were ovariectomized (OVX) after mammary tumor development and were then placed into one of three treatment groups: positive-control (OVX+ estradiol implant), genistein (OVX+ dietary genistein), and negative-control (OVX alone). Tumors were distinguished as malignant or benign by histopathological examination and were further characterized as either estrogen-dependent or independent using immunohistochemistry to identify the presence of both estrogen receptor alpha (ERalpha) and the progesterone receptor (PR). Genistein at 750 ppm increased the weight of estrogen-dependent adenocarcinomas in ovariectomized rats compared to the negative-control animals. Genistein treatment also resulted in a higher percentage of proliferative cells in tumors and increased uterine weights when compared to negative-control animals. Collectively, these effects are likely due to the estrogenic activity of genistein. Plasma genistein concentrations in animals fed the isoflavone-containing diet were at physiological levels relevant to human exposure. Estradiol concentrations in ovariectomized animals not receiving an estradiol supplement were similar to those observed in postmenopausal women. These data suggest that in an endogenous estrogen environment similar to that of a postmenopausal woman, dietary genistein can stimulate the growth of chemically induced estrogen-dependent mammary tumors. |
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Title:
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Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women's Health Initiative Cohort Study. |
| Author(s): |
McTiernan A, Kooperberg C, White E, Wilcox S, Coates R, Adams-Campbell LL, Woods N, Ockene J; Women's Health Initiative Cohort Study. |
| CONTEXT: Women who are physically active have a decreased risk for breast cancer, but the types, amounts, and timing of activity needed are unknown. OBJECTIVE: To prospectively examine the association between current and past recreational physical activity and incidence of breast cancer in postmenopausal women.Design, Setting, and PATIENTS: Prospective cohort study in 74 171 women aged 50 to 79 years who were recruited by 40 US clinical centers from 1993 through 1998. MAIN OUTCOME MEASURE: Incident invasive and in situ breast cancer. RESULTS: We documented 1780 newly diagnosed cases of breast cancer over a mean follow-up of 4.7 years. Compared with less active women, women who engaged in regular strenuous physical activity at age 35 years had a 14% decreased risk of breast cancer (relative risk [RR], 0.86; 95% confidence interval [CI], 0.78-0.95). Similar but attenuated findings were observed for strenuous physical activity at ages 18 years and 50 years. An increasing total current physical activity score was associated with a reduced risk for breast cancer (P =.03 for trend). Women who engaged in the equivalent of 1.25 to 2.5 hours per week of brisk walking had an 18% decreased risk of breast cancer (RR, 0.82; 95% CI, 0.68-0.97) compared with inactive women. Slightly greater reduction in risk was observed for women who engaged in the equivalent of 10 hours or more per week of brisk walking. The effect of exercise was most pronounced in women in the lowest tertile of body mass index (BMI) (<24.1), but also was observed for women in the middle tertile of BMI (24.1-28.4). CONCLUSIONS: These data suggest that increased physical activity is associated with reduced risk for breast cancer in postmenopausal women, longer duration provides most benefit, and that such activity need not be strenuous. |
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Title:
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Antioxidant supplements and risk of breast cancer recurrence and breast cancer-related mortality among postmenopausal women. |
| Author(s): |
Fleischauer AT, Simonsen N, Arab L. |
| Despite widespread use, only a few clinical or epidemiological studies have examined the relationship between antioxidant supplements and risk of breast cancer recurrence or breast cancer-related mortality. We used proportional hazards and logistic regression modeling to estimate rate ratios and odds ratios (ORs) for recurrence and mortality among 385 postmenopausal women diagnosed with breast cancer between 1986 and 1988 enrolled into a case-control study on diet and cancer. Women were recontacted with a single questionnaire to ascertain the use of nutritional supplements during 12-14 yr of follow-up time. In multivariable models, antioxidant supplement users compared with nonusers were less likely to have a breast cancer recurrence or breast cancer-related death (OR = 0.54, 95% CI = 0.27-1.04). Vitamin E supplements showed a modest protective effect when used for more than 3 yr (OR = 0.33, 95% CI = 0.10-1.07). Premorbid dietary intake of vitamins C or E from diet, supplements, or both showed no relationship with risk. Risks of recurrence and disease-related mortality were reduced among women using vitamin C and vitamin E supplements for more than 3 yr. Recall bias among proxy respondents for women who died during follow-up may have contributed to these findings. This study provides limited support for the hypothesis that antioxidant supplements may reduce the risk of breast cancer recurrence or breast cancer-related mortality. |
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Title:
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Dose response study of conjugated fatty acid derived from safflower oil on mammary and colon carcinogenesis pretreated with 7,12-dimethylbenz[a]anthracene (DMBA) and 1,2-dimethylhydrazine (DMH) in female Sprague-Dawley rats. |
| Author(s): |
Cheng JL, Futakuchi M, Ogawa K, Iwata T, Kasai M, Tokudome S, Hirose M, Shirai T. |
| To clarify the chemopreventive effects of conjugated fatty acid derived from safflower oil (CFA-S), rich in conjugated linoleic acid (CLA), on mammary and colon carcinogenesis, 6 week old female Sprague-Dawley (SD) rats received diet containing 0.01, 0.05, 0.1, 1, or 2% CFA-S subsequent to five times subcutaneous injections of 1,2-dimethyl-hydrazine (DMH) at a dose of 40 mg/kg b.w. and a single 50 mg/kg b.w. intragastric application of 7,12-dimethylbenz[a]anthracene (DMBA) during the first 11 days. The experiment was terminated at week 36. Numbers of mammary tumors, colon aberrant crypt foci (ACF), and proliferative indices of mammary tumors, and colon epithelium were analyzed. The 1% dose was found to be optimal for suppression of carcinogenesis in both target organs, a good correlation being noted with between data for cell proliferation. These results suggest that a diet containing appropriate levels of CFA-S may be useful for prevention of mammary and colon cancer. |
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Title:
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Urinary equol excretion in relation to 2-hydroxyestrone and 16alpha-hydroxyestrone concentrations: an observational study of young to middle-aged women. |
| Author(s): |
Atkinson C, Skor HE, Dawn Fitzgibbons E, Scholes D, Chen C, Wahala K, Schwartz SM, Lampe JW. |
| Approximately one-third to one-half of individuals harbor the colonic bacteria that are capable of metabolizing the soy isoflavone daidzein to equol. Results of prior studies suggest beneficial effects of producing equol in relation to breast cancer risk, potentially through effects on endogenous hormones. High urinary excretion of 2-hydroxyestrone (2-OH E(1)) relative to 16alpha-hydroxyestrone (16alpha-OH E(1)) has been associated with a reduced risk of breast cancer. In this pilot study we examined associations between urinary excretion of equol and 2-OH E(1), 16alpha-OH E(1), and their ratio, and investigated whether excretion of these estrogen metabolites differed between two samples collected 48h apart. Isoflavones (genistein, daidzein, O-desmethylangolensin (ODMA), and equol) were measured in two overnight urines from 126 women. Excretion of 2-OH E(1) and 16alpha-OH E(1) were measured in the first overnight urine from all 126 women and in the second overnight urine from 30 of these women; there were no significant differences between samples collected 48h apart in excretion of 2-OH E(1) or 16alpha-OH E(1) (P=0.75 and 0.17, respectively). Among all women, correlations between total isoflavone excretion (sum of genistein, daidzein, ODMA, and equol) and estrogen metabolites were non-significant (P>0.05). Among women with detectable levels of equol, total isoflavone excretion was significantly positively correlated with 16alpha-OH E(1) (r=0.32, P=0.02), but was not correlated with 2-OH E(1) or 2-OH E(1):16alpha-OH E(1) ratio (r=0.21, P=0.14, and r=-0.05, P=0.70, respectively). Equol excretion (adjusted for other isoflavone excretion) was significantly positively correlated with 2-OH E(1):16alpha-OH E(1) ratio (r=0.38, P=0.005), but was not correlated with 2-OH E(1) or 16alpha-OH E(1) (r=0.15, P=0.29, and r=-0.17, P=0.24, respectively). The finding that equol excretion, but not total isoflavone excretion, correlated positively with the 2-OH E(1):16alpha-OH E(1) ratio suggests that the colonic bacterial profile associated with equol production may be involved in estrogen metabolism, and may therefore possibly influence breast cancer risk. |
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Title:
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Indole-3-carbinol is a negative regulator of estrogen. |
| Author(s): |
Auborn KJ, Fan S, Rosen EM, Goodwin L, Chandraskaren A, Williams DE, Chen D, Carter TH. |
| Studies increasingly indicate that dietary indole-3-carbinol (I3C) prevents the development of estrogen-enhanced cancers including breast, endometrial and cervical cancers. Epidemiological, laboratory, animal and translational studies support the efficacy of I3C. Whereas estrogen increases the growth and survival of tumors, I3C causes growth arrest and increased apoptosis and ameliorates the effects of estrogen. Our long-range goal is to best use I3C together with other nutrients to achieve maximum benefits for cancer prevention. This study examines the possibility that induction of growth arrest in response to DNA damage (GADD) in genes by diindolylmethane (DIM), which is the acid-catalyzed condensation product of I3C, promotes metabolically stressed cancer cells to undergo apoptosis. We evaluated whether genistein, which is the major isoflavonoid in soy, would alter the ability of I3C/DIM to cause apoptosis and decrease expression driven by the estrogen receptor (ER)-alpha. Expression of GADD was evaluated by real-time reverse transcription-polymerase chain reaction. Proliferation and apoptosis were measured by a mitochondrial function assay and by fluorescence-activated cell sorting analysis. The luciferase reporter assay was used to specifically evaluate expression driven by ER-alpha. The estrogen-sensitive MCF-7 breast cancer cell line was used for these studies. We show a synergistic effect of I3C and genistein for induction of GADD expression, thus increasing apoptosis, and for decrease of expression driven by ER-alpha. Because of the synergistic effect of I3C and genistein, the potential exists for prophylactic or therapeutic efficacy of lower concentrations of each phytochemical when used in combination. |
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Title:
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Indole-3-carbinol and 3-3'-diindolylmethane antiproliferative signaling pathways control cell-cycle gene transcription in human breast cancer cells by regulating promoter-Sp1 transcription factor interactions. |
| Author(s): |
Firestone GL, Bjeldanes LF. |
| Indole-3-carbinol (I3C), a compound that occurs naturally in Brassica vegetables such as cabbage and broccoli, can induce a G1 cell-cycle arrest of human MCF-7 breast cancer cells that is accompanied by the selective inhibition of cyclin-dependent kinase 6 (Cdk6) expression and stimulation of p21(Waf1/Cip1) gene expression. Construction and transfection of a series of promoter-reporter plasmids demonstrate that the indole-regulated changes in Cdk6 and p21(Waf1/Cip1) levels are due to specific effects on their corresponding promoters. Mutagenic analysis reveals that I3C signaling targets a composite transcriptional element in the Cdk6 promoter that requires both Sp1 and Ets transcription factors for transactivation function. Analysis of protein-DNA complexes formed with nuclear proteins isolated from I3C-treated and -untreated cells demonstrates that the Sp1 DNA element in the Cdk6 promoter interacts with an I3C-inhibited protein-protein complex that contains the Sp1 transcription factor. In indole-treated cells, a fraction of [(3)H]I3C was converted into its natural diindole product (3)H-labeled 3-3'-diindolylmethane ([(3)H]DIM), which accumulates in the nucleus; this suggests that DIM may have a role in the transcriptional activities of I3C. Mutagenic analysis of the p21(Waf1/Cip1) promoter reveals that in transfected breast cancer cells, DIM (as well as I3C) stimulates p21(Waf1/Cip1) transcription through an indole-responsive region of the promoter that contains multiple Sp1 consensus sequences. Furthermore, DIM treatment regulates the presence of a nuclear Sp1 DNA-binding activity. Our results demonstrate that both the Cdk6 and p21(Waf1/Cip1) promoters are newly defined downstream targets of the indole-signaling pathway, and that the observed transcriptional effects are due to a combination of the cellular activities of I3C and DIM |
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Title:
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Inositol hexaphosphate (IP6) enhances the anti-proliferative effects of adriamycin and tamoxifen in breast cancer. |
| Author(s): |
Tantivejkul K, Vucenik I, Eiseman J, Shamsuddin AM. |
| The current treatment of breast carcinomas recognizes the importance of combination therapy in order to increase efficacy and decrease side effects of conventional chemotherapy. Inositol hexaphosphate (IP6), a naturally occurring polyphosphorylated carbohydrate, has shown a significant anti-cancer effect in various in vivo and in vitro models, including breast cancer. In this study, we investigated the in vitro growth inhibitory activity of IP6 in combination with adriamycin or tamoxifen, against three human breast cancer cell lines: estrogen receptor (ER) alpha-positive MCF-7, ER alpha-negative MDA-MB 231 and adriamycin-resistant MCF-7 (MCF-7/Adr) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Much lower concentrations of IP6 were required after 96 h of treatment to inhibit the growth of MCF-7/Adr cells than MCF-7 cells; the IC50 for MCF-7/Adr cells was 1.26 mM compared to 4.18 mM for MCF-7 cells. The ER-negative MDA-MB 231 cells were also highly sensitive to IP6 with IC50 being 1.32 mM. To determine the effects of IP6 in combination with either adriamycin or tamoxifen, the median effect principle and Webb's fraction method were used to determine the combination index (CI) and the statistical differences. Growth suppression was markedly increased when IP6 was administered prior to the addition of adriamycin, especially against MCF-7 cells (CI = 0.175 and p < 0.0001). Synergism was also observed when IP6 was administered after tamoxifen in all three cell lines studied (CI = 0.343, 0.701 and 0.819; p < 0.0001, p = 0.0003 and 0.0241 for MCF-7/Adr, MCF-7 and MDA-MB 231, respectively). The growth of primary culture of breast cancer cells from patients was inhibited by IP6 with LC50 values ranging from 0.91 to 5.75 mM (n = 10). Our data not only confirm that IP6 alone inhibits the growth of breast cancer cells; but it also acts synergistically with adriamycin or tamoxifen, being particularly effective against ER alpha-negative cells and adriamycin-resistant cell lines. |
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Title:
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Indole-3-carbinol and 3,3'-diindolylmethane induce apoptosis in human prostate cancer cells. |
| Author(s): |
Nachshon-Kedmi M, Yannai S, Haj A, Fares FA. |
| Cruciferous vegetables contain glucobrassicin which, during metabolism, yields indole-3-carbinol (I3C). In a low pH environment I3C is converted into polymeric products, among which 3,3'-diindolylmethane (DIM) is the main one. The apoptotic effects of I3C and DIM were exhibited in human breast cancer cells. The objectives of this study were: (a) examination of the potential effects of I3C and DIM on the proliferation and induction of apoptosis in human prostate cancer cell lines with different p53 status; (b) to try to characterise the mechanism(s) involved in these effects. Our results indicate that both indole derivatives suppress the growth of these cells in a dose- and time-dependent manner, by inducing apoptosis. It appears that these indolic compounds may offer effective means against prostate cancer. Induction of apoptosis was p53-independent. Moreover, the indole derivatives employed did not affect the levels of bcl-2, bax and fasL. |
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Title:
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Anti-angiogenic activity of conjugated linoleic acid on basic fibroblast growth factor-induced angiogenesis. |
| Author(s): |
Moon EJ, Lee YM, Kim KW. |
| Conjugated linoleic acid (CLA) is a potent inhibitor of mammary carcinogenesis. Cancer cells produce various angiogenic factors which stimulate host vascular endothelial cell mitogenesis and chemotaxis for their growth and metastasis. Basic fibroblast growth factor (bFGF) is a potent angiogenic factor that is expressed in many tumors. In this study, we found that CLA decreased bFGF-induced endothelial cell proliferation and DNA synthesis in a dose-dependent manner. However, CLA did not inhibit endothelial cell migration. Furthermore, CLA showed a potent inhibitory effect on embryonic vasculogenesis and bFGF-induced angiogenesis in vivo. Collectively, these results suggest that CLA selectively inhibits the active proliferating endothelial cells induced by bFGF, which may explain its anti-carcinogenic properties in vivo. |
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Title:
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In vitro effects of the Cimicifuga racemosa extract BNO 1055 |
| Author(s): |
Jarry, H., Metten, M., Spengler, B., Christoffel, V. Wuttke, W. |
| OBJECTIVES: Extracts of Black cohosh (Cimicifuga racemosa or CR) have been used for the treatment of climacteric complaints since decades. Efficacy, particularly concerning neurovegetative and psychic symptoms, has been proven in clinical trials. As active principle yet unknown substances with selective estrogen receptor modulator (SERM) activity are assumed. Recently, evidence arose that CR may also contain dopaminergic compounds, which may contribute to the therapeutic activity of the extract. METHODS: Two subtypes of the estrogen receptor (ERalpha and ERbeta) are known. To examine, whether active substances of CR extract BNO 1055 (which is contained in Klimadynon(R) and Menofem(R)) bind to either of the two estrogen receptors, subtype-specific estrogen receptor ligand-binding assays with recombinant ERalpha or ERbeta were conducted. A ligand-binding assay with recombinant dopamine D(2)-receptor protein was employed to assess possible dopaminergic activity in the CR extract BNO 1055. RESULTS: While a displacement of radiolabeled estradiol from binding sites of a cytosol preparation from procine and human endometrium by CR extract BNO 1055 was shown no such displacement was achieved when either ERalpha or ERbeta protein was used as ligands for tracer. Dopaminergic activity in the CR extract BNO 1055 could be demonstrated with the D(2)-receptor assay. A countercurrent chromatography resulted in a separation of estrogenic and dopaminergic activity in two distinct fractions. CONCLUSIONS: It is suggested that not yet identified substances in the CR extract BNO 1055 bind to a yet unknown estrogen-binding site in the endometrium. Also, yet unknown dopaminergic compounds may contribute to the pharmacological profile of CR extract BNO 1055. |
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Title:
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Familial Risks, Early-Onset Breast Cancer, and BRCA1 and BRCA2 Germline Mutations. |
| Author(s): |
Dite GS, Jenkins MA, Southey MC, Hocking JS, Giles GG, McCredie MR, Venter DJ, Hopper JL. |
| BACKGROUND: Having a family history of breast cancer, particularly if it involves early-onset disease, is a risk factor for breast cancer, but little is known about specific causes of this association. Consequently, we studied mothers, sisters, and aunts of an age-stratified sample of 1567 unselected case patients diagnosed with breast cancer before age 60 years, recruited to a population-based, case-control-family study, in which case patients, control subjects, and their relatives were administered the same questionnaire. METHODS: Extensive BRCA1 and BRCA2 mutation testing was carried out for 788 case patients diagnosed before age 40 years, including manual sequencing of DNA from 72 patients with two or more affected relatives. Standardized morbidity ratios, age-specific cumulative risks, and hazard ratios were calculated for groupings of relatives. RESULTS: Cumulative risks of breast cancer to age 50 years in the sisters, mothers, and aunts of the case patients, respectively, were 6, 3, and 2 times the population risk if the case patient was younger than age 40 years at diagnosis but were considerably lower if the case patient was older at diagnosis. When relatives of the case patients with a BRCA1 or BRCA2 mutation were excluded, these risks fell by, at most, 20%. Sisters and aunts, but not mothers, who had an additional first-degree relative with breast cancer were at increased risk, and the risk was greater when that relative was younger at diagnosis. Hazard ratios were 10.7 (95% confidence interval [CI] = 4.2 to 26.8) for sisters and 4.2 (95% CI = 2.2 to 8.1) for aunts, if the relative was aged 40 years at diagnosis. Fewer than one-third of the excess of breast cancers in relatives of case patients diagnosed before age 40 years that are attributed to familial factors are BRCA1- or BRCA2-related. CONCLUSION: Mutations in genes other than BRCA1 and BRCA2 may be associated with a high risk of breast cancer, especially in young women. |
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Title:
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Colonic anti-inflammatory mechanisms of conjugated linoleic acid. |
| Author(s): |
BASSAGANYA-RIERA J, HONTECILLAS R, BEITZ DC. |
| Conjugated linoleic acid (CLA) is a mixture of positional (e.g. 7,9; 9,11; 10,12; 11,13) and geometric (cis or trans) isomers of octadecadienoic acid. This compound was first shown to prevent mammary carcinogenesis in murine models. Later investigations uncovered a number of additional health benefits, including decreasing atherosclerosis and inflammation while enhancing immune function. The mechanisms of action underlying these biological properties are not clearly understood. The aim of this review is to highlight recent advances in CLA research related to experimental inflammatory bowel disease. In addition, two possible mechanisms of action (i.e. endoplasmic and nuclear) were discussed in detail in the context of enteric inflammatory disorders. Conjugated linoleic acid was first implicated in down-regulating the generation of inducible eicosanoids (i.e. PGE(2) and LTB(4)) involved in early micro-inflammatory events (endoplasmic). More recently, CLA has been shown to modulate the expression of genes regulated by peroxisome proliferator-activated receptors (PPARs; nuclear). In pigs, prolonged dietary CLA treatment stimulated the expression of PPAR-gamma in the muscle. Thus, evidence supporting both mechanistic theories of CLA acting through eicosanoid synthesis and PPAR activity is available. The further understanding of the anti-inflammatory mechanisms of action of CLA may yield novel nutritional therapies for enteric inflammation. |
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Title:
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Dietary supplementation with isolated soy protein reduces metastasis of mammary carcinoma cells in mice. |
| Author(s): |
Yan L, Li D, Yee JA. |
| The present study investigated the effect of dietary supplementation with isolated soy protein (ISP) on pulmonary metastasis of carcinoma cells from primary mammary tumors induced by orthotopic injection of 4526 murine mammary carcinoma cells in female BALB/c mice. Three diets were compared: a basal AIN-93G diet and the basal diet supplemented with 10% or 20% ISP. After three weeks on the experimental diets, each mouse was injected 4 x 10(5) carcinoma cells into the right inguinal mammary fat pad. The primary tumors were excised when they reached a size of 1.0 cm in diameter. After surgery, mice were maintained on their respective diets for another three weeks. At necropsy, the incidence of metastasis, the number and size of macroscopic tumors, and the number of microscopic tumors in the lungs were determined. The incidence of mice with macroscopically visible tumors was 93%, 76%, and 67%, and the median number of macroscopic tumor was 5, 2, and 1 for the control, 10%, and 20% ISP groups (P < or = 0.05, 20% ISP vs. control). The median cross-sectional area of the macroscopic tumors was 0.93 mm2, 0.80 mm2, and 0.31 mm2, and the median volume was 0.73 mm3, 0.56 mm3, and 0.14 mm3 for the control, 10%, and 20% ISP groups (P < or = 0.01, 20% ISP vs. control). Histological examination revealed fewer microscopically detectable tumors in the ISP groups compared with the control. These results demonstrated that dietary supplementation with ISP reduced pulmonary metastasis of carcinoma cells from primary mammary tumors in BALB/c mice. |
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Title:
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Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by fermented soy milk. |
| Author(s): |
Chang WH, Liu JJ, Chen CH, Huang TS, Lu FJ. |
| The effect of a fermented soy milk product (FSP) on various human breast carcinoma cell lines was investigated, and it was shown to have a growth-inhibitory effect, especially on MCF-7 cells. Thus the MCF-7 cell line was used to study the mechanism of action. In female severe combined immune deficiency mice implanted with MCF-7 cells, pretreatment with FSP significantly inhibited tumor growth. The inhibitory effect of FSP on MCF-7 cells seemed to be caused by the additive effects of a wide variety of constituents. The active components of FSP are mainly in the water phase, and the lipid-soluble fraction, which includes the soy isoflavones such as genistein and daidzein, is relatively ineffective. A variety of methods were used to demonstrate that FSP caused apoptotic cell death in MCF-7 cells. FSP induced generation of reactive oxygen species (ROS). Growth inhibition and ROS generation induced by FSP could be inhibited by catalase and deferoxamine, indicating that the ROS production probably was the cause of this apoptotic cell death. This study suggests that FSP retards tumor growth in vivo and can trigger apoptosis in vitro. It may, therefore, be a potential nutritional supplement in chemotherapy. |
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Title:
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High-folate diets and breast cancer survival in a prospective cohort study. |
| Author(s): |
Sellers TA, Alberts SR, Vierkant RA, Grabrick DM, Cerhan JR, Vachon CM, Olson JE, Kushi LH, Potter JD. |
| Recent evidence suggests that adequate dietary folate may attenuate the risk of breast cancer associated with intake of alcohol. However, patients with breast cancer have been commonly treated with antifolate chemotherapies. The present analysis was performed to test the hypothesis that high folate intake may diminish the effectiveness of chemotherapy and, therefore, adversely influence survival. Women at risk of postmenopausal breast cancer (n = 37,105) participated in the Iowa Women's Health Study. Total folate intake (diet + supplements) was estimated from a food frequency questionnaire administered at baseline in 1986 and categorized into tertiles. From all incident breast cancer cases ascertained in the cohort, we selected those with a diagnosis between 1986 and 1994, chemotherapy as first course of treatment, and adequate diet assessment. Mortality was determined through the State Health Registry of Iowa and the National Death Index. Cox regression was used to estimate survival while adjusting for important covariates. Through 14 yr of follow-up, 80 deaths occurred among the 177 breast cancer cases treated with chemotherapy. Among these patients, high folate intake was not associated with worse survival. After adjustment for age, extent of disease, total calories, alcohol, and estrogen receptor status, women with total folate intake in the highest tertile had a mortality risk ratio of 0.88 (95% confidence interval = 0.44-1.76) compared with cases in the lowest tertile of folate. These findings, although preliminary, afford some reassurance that folate supplementation is unlikely to have a significant adverse effect on survival after chemotherapy for breast cancer. |
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Title:
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Role of GTP-binding proteins in reversing the antiproliferative effects of tocotrienols in preneoplastic mammary epithelial cells. |
| Author(s): |
Sylvester PW, Nachnani A, Shah S, Briski KP. |
| Tocotrienols are a subclass of vitamin E compounds that display potent anticancer activity. Determining the anticancer mechanism of action of tocotrienols will provide essential information necessary for understanding the potential health benefits of these compounds in reducing the risk of breast cancer in women. Epidermal growth factor (EGF) is a potent mitogen for normal and neoplastic mammary epithelial cells. Initial events in EGF-receptor (EGF-R) mitogenic-signalling are G-protein activation, stimulation of adenylyl cyclase and cyclic AMP (cAMP) production. Studies were conducted to determine if the antiproliferative effects of tocotrienols are associated with reduced EGF-induced G-protein and cAMP-dependent mitogenic signalling. Preneoplastic CL-S1 mouse mammary epithelial cells were grown in culture and maintained on serum-free media containing 0-25 micro mol/L tocotrienol-rich fraction of palm oil and/or different doses of pharmacological agents that alter intracellular cAMP levels. Tocotrienol-induced effects on EGF-receptor levels of tyrosine kinase activity, as well as EGF-dependent mitogen-activated pathway kinase (MAPK) and Akt activation, were determined by western blot analysis. Results demonstrate that the antiproliferative effects of tocotrienols in preneoplastic mammary epithelial cells do not reflect a reduction in EGF-receptor mitogenic responsiveness, but rather, result from an inhibition in early post-receptor events involved in cAMP production upstream from EGF-dependent MAPK and phosphoinositide 3-kinase/Akt mitogenic signalling. In summary, these data further characterise the mechanism of action of tocotrienols in suppressing preneoplastic mammary epithelial cell proliferation, and advance the current understanding of the potential health benefits of these compounds in reducing the risk of breast cancer in women. |
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Title:
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Frequency of use of complementary and alternative medicine in women with breast cancer. |
| Author(s): |
Lengacher CA, Bennett MP, Kip KE, Keller R, LaVance MS, Smith LS, Cox CE. |
| PURPOSE/OBJECTIVES: To estimate the frequency of use of complementary and alternative medicine (CAM) therapies among women diagnosed with breast cancer and to identify demographic and clinical factors associated with CAM use in these patients. DESIGN: A descriptive, cross-sectional survey. SAMPLE: A convenience sample of 105 predominantly Caucasian women (mean age = 59 years) with a diagnosis of breast cancer was recruited from the Tampa Bay area and a rural midwestern area. METHODS: Utilizing the "Use of Complementary Therapies Survey," frequency of CAM use was calculated for 33 individual therapies listed on the survey and among three survey-defined subscales of CAM therapies (i.e., diet and nutritional supplements, stress-reducing techniques, and traditional and ethnic medicines). MAIN RESEARCH VARIABLES: Use of CAM therapies and types of treatment in women with breast cancer. FINDINGS: Among diet and nutritional supplements, 64% of all participants reported regular use of vitamins and minerals and 33% regularly used antioxidants, herbs, and health foods. Among stress-reducing techniques, 49% of all participants regularly used prayer and spiritual healing, followed by support groups (37%) and humor or laughter therapy (21%). Traditional and ethnic medicine therapies rarely were used with the exception of massage, which 27% of all participants used at least once after diagnosis. More frequent CAM use was observed among study participants who had undergone previous chemotherapy treatment and those with more than a high school education. Also, being less satisfied with their primary physician was associated with patients' more frequent CAM use. CONCLUSIONS: CAM use is increasing among women with breast cancer, and frequency of specific use according to type of CAM is higher than what has been reported in other studies. Use increased in patients who had undergone chemotherapy and in those with a high school education. IMPLICATIONS FOR NURSING: Oncology nurses are in a key position to identify what treatments patients are using and implement CAM therapies that can be helpful to relieve patient symptoms related to treatment and psychological distress. |
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Title:
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Black cohosh (Cimicifuga racemosa L.) protects against menadione-induced DNA damage through scavenging of reactive oxygen species: bioassay-directed isolation and characterization of active principles. |
| Author(s): |
Burdette JE, Chen SN, Lu ZZ, Xu H, White BE, Fabricant DS, Liu J, Fong HH, Farnsworth NR, Constantinou AI, Van Breemen RB, Pezzuto JM, Bolton JL. |
| The roots/rhizomes of Cimicifuga racemosa L. (Nutt.) (black cohosh) have traditionally been used to treat menopausal symptoms through an unknown mechanism of action. In an effort to determine if black cohosh had additional health benefits, methanol extracts were investigated for their potential to scavenge reactive oxygen species and to protect against menadione-induced DNA damage. These extracts effectively scavenged 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals. In addition, the extracts showed dose-dependent decreases in DNA single-strand breaks and oxidized bases induced by the quinone menadione using the comet (single-cell gel electrophoresis assay) and fragment length associated repair enzyme assays, respectively. Bioassay-directed fractionation of the methanolic extracts using the DPPH assay as a monitor led to the isolation of nine antioxidant active compounds: caffeic acid (1), methyl caffeate (2), ferulic acid (3), isoferulic acid (4), fukinolic acid (5), cimicifugic acid A (6), cimicifugic acid B (7), cimicifugic acid F (8), cimiracemate A (9), and cimiracemate B (10). Six of these antioxidants were found to reduce menadione-induced DNA damage in cultured S30 breast cancer cells with the following order of potency: methyl caffeate (2) > caffeic acid (1) > ferulic acid (3) > cimiracemate A (9) > cimiracemate B (10) > fukinolic acid (5). These data suggest that black cohosh can protect against cellular DNA damage caused by reactive oxygen species by acting as antioxidants. |
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Title:
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Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. |
| Author(s): |
Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, Raz A. |
| BACKGROUND: The role of dietary components in cancer progression and metastasis is an emerging field of clinical importance. Many stages of cancer progression involve carbohydrate-mediated recognition processes. We therefore studied the effects of high pH- and temperature-modified citrus pectin (MCP), a nondigestible, water-soluble polysaccharide fiber derived from citrus fruit that specifically inhibits the carbohydrate-binding protein galectin-3, on tumor growth and metastasis in vivo and on galectin-3-mediated functions in vitro. METHODS: In vivo tumor growth, angiogenesis, and metastasis were studied in athymic mice that had been fed with MCP in their drinking water and then injected orthotopically with human breast carcinoma cells (MDA-MB-435) into the mammary fat pad region or with human colon carcinoma cells (LSLiM6) into the cecum. Galectin-3-mediated functions during tumor angiogenesis in vitro were studied by assessing the effect of MCP on capillary tube formation by human umbilical vein endothelial cells (HUVECs) in Matrigel. The effects of MCP on galectin-3-induced HUVEC chemotaxis and on HUVEC binding to MDA-MB-435 cells in vitro were studied using Boyden chamber and labeling assays, respectively. The data were analyzed by two-sided Student's t test or Fisher's protected least-significant-difference test. RESULTS: Tumor growth, angiogenesis, and spontaneous metastasis in vivo were statistically significantly reduced in mice fed MCP. In vitro, MCP inhibited HUVEC morphogenesis (capillary tube formation) in a dose-dependent manner. In vitro, MCP inhibited the binding of galectin-3 to HUVECs: At concentrations of 0.1% and 0.25%, MCP inhibited the binding of galectin-3 (10 micro g/mL) to HUVECs by 72.1% (P =.038) and 95.8% (P =.025), respectively, and at a concentration of 0.25% it inhibited the binding of galectin-3 (1 micro g/mL) to HUVECs by 100% (P =.032). MCP blocked chemotaxis of HUVECs toward galectin-3 in a dose-dependent manner, reducing it by 68% at 0.005% (P<.001) and inhibiting it completely at 0.1% (P<.001). Finally, MCP also inhibited adhesion of MDA-MB-435 cells, which express galectin-3, to HUVECs in a dose-dependent manner. CONCLUSIONS: MCP, given orally, inhibits carbohydrate-mediated tumor growth, angiogenesis, and metastasis in vivo, presumably via its effects on galectin-3 function. These data stress the importance of dietary carbohydrate compounds as agents for the prevention and/or treatment of cancer. |
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Title:
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Interaction of dietary folate intake, alcohol, and risk of hormone receptor-defined breast cancer in a prospective study of postmenopausal women. |
| Author(s): |
Sellers TA, Vierkant RA, Cerhan JR, Gapstur SM, Vachon CM, Olson JE, Pankratz VS, Kushi LH, Folsom AR. |
| Alcohol intake is an established risk factor for breast cancer, but the underlying mechanism remains unknown. Four recent studies have described interactions of alcohol and low folate intake. We examined this interaction on the risk of postmenopausal breast cancer stratified by tumor receptor status for estrogen (ER) and progesterone (PR). The Iowa Women's Health Study is a prospective cohort study of 34,393 at-risk women. Alcohol use and folate intake from diet and supplements were estimated at baseline in 1986 through a semiquantitative food frequency questionnaire. Through 1999, 1,875 cases of breast cancer were identified through linkage to the Iowa Surveillance, Epidemiology, and End Results registry. Compared with nondrinkers with folate intakes above the 50(th) percentile, women with low folate and high alcohol were at 1.43-fold greater risk (1.02-2.02). When stratified by tumor receptor status for ER or PR, the risks for low folate/high alcohol were 2.1 (1.18-3.85), 1.0 (0.76-1.42), 1.2 (0.88-1.70), and 1.2 (0.69-2.02) for ER-, ER+, PR+, and PR- tumors, respectively. Because the results were limited primarily to ER- tumors, one plausible interpretation of these data is that alcohol influences breast cancer through its metabolite, acetaldehyde, rather than through effects on ER levels and receptor-mediated pathways. |
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Title:
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Conjugated linoleic acids (CLAs) regulate the expression of key apoptotic genes in human breast cancer cells. |
| Author(s): |
Majumder B, Wahle KW, Moir S, Schofield A, Choe SN, Farquharson A, Grant I, Heys SD. |
| Conjugated linoleic acid (CLA) reduces mammary tumorigenesis in rodent models, induces apoptosis in rodent mammary tumor cell lines, and decreases expression of antiapoptotic bcl-2 in rat mammary tissue. This investigation focused on the cell mechanisms underlying the antitumor effects of CLA. Changes (mRNA, protein) in expression of major proapoptotic p53, p21WAF1/CIP1, bax, bcl-Xs genes, and the antiapoptotic bcl-2 gene were observed in malignant MCF-7 and MDA-MB-231 cells and in benign MCF-10a human mammary tumor cells in culture. CLA, but not linoleic acid (LA), inhibited proliferation in all cells; CLA mix was most effective. CLA increased DNA damage (apoptosis). CLA increased mRNA expression of p53 and p21WAF1/CIP1 (three- to fivefold and twofold, respectively) but either decreased bcl-2 by 20-30% or had no effect in MCF-7 and MCF-10a cells, respectively; protein expression reflected mRNA values. In MDA-MBA-231 (mutant p53) cells, mRNA for p53 was not changed, but p21WAF1/CIP1 and bcl-2 mRNA was increased. Protein expression largely reflected mRNA changes but, surprisingly, CLA completely suppressed mutant p53 protein in MDA-MB-231 cells. Apparent antiapoptotic effects of increased bcl-2 expression in MDA-MBA-231 cells were countered by increased proapoptotic p21WAF1/CIP1, Bax, and Bcl-Xs proteins. Findings indicate that CLA elicits mainly proapoptotic effects in human breast tumor cells through both p53-dependent and p53-independent pathways, according to cell type. |
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Title:
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Dietary intake of selected fatty acids, cholesterol and carotenoids and estrogen receptor status in premenopausal breast cancer patients. |
| Author(s): |
Jakovljevic J, Touillaud MS, Bondy ML, Singletary SE, Pillow PC, Chang S. |
| Although a wealth of research has focused on the influence of diet on breast cancer risk, the relationships between dietary factors and tumor characteristics of breast cancer, like estrogen receptor (ER) status, are not well characterized. In a case-case study, we evaluated self-reported dietary intake for five individual carotenoids, selected fatty acids, and cholesterol 1 year before diagnosis in 34 premenopausal breast cancer patients with ER-negative tumors and 86 premenopausal breast cancer patients with ER-positive tumors from The University of Texas M. D. Anderson Cancer Center. In multivariate logistic regression analysis adjusted for age, body mass index, and ethnicity, high intakes of linoleic acid were associated with more than a threefold greater risk of ER-negative disease than ER-positive disease (odds ratio (OR) = 3.48, 95% confidence interval (CI) = 1.42-8.54), whereas high cholesterol intake was associated with lower risk of ER-negative disease (OR = 0.35, 95% CI = 0.14-0.92). In a model evaluating carotenoids, selected fatty acids, and cholesterol together, the association with high intake of linoleic acid remained statistically significant (OR = 3.96,95% CI = 1.53-10.25), while those for high intake of cholesterol (OR = 0.38, 95% CI = 0.14-1.03) and low intake of cryptoxanthin (OR = 0.43, 95% CI = 0.17-1.06) were of marginal significance. While no striking associations were observed for the intakes of total carotenoids, selected fatty acids, and cholesterol, our analysis revealed an association for the consumption of a specific fatty acid (i.e., linoleic acid), suggesting dietary influence of this factor on ER status in premenopausal breast cancer patients. However, larger studies are needed to clarify the role of micronutrients in ER status in breast cancer. |
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Title:
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Lack of promotion of estrogen-dependent mammary gland tumors in vivo by an isopropanolic Cimicifuga racemosa extract. |
| Author(s): |
Freudenstein J, Dasenbrock C, Nisslein T. |
| Cimicifuga racemosa (CR) is widely used in the treatment of menopausal symptoms. Mechanistic studies suggest that unlike hormone-replacement therapy, CR does not stimulate estrogen-receptor positive breast cancer cells. To evaluate CR safety, we performed an in vivo investigation of a clinically tested isopropanolic CR extract. Mammary tumors were induced in Sprague Dawley rats (n = 75) by the application of 7,12-dimethylbenz[a]anthracene. Five to nine weeks later, the animals were ovariectomized, allowed to recover, and administered daily doses of CR extract (0.714, 7.14, or 71.4 mg/kg body weight per day) or control substances (estrogen/positive control: 450 microg/kg/day mestranol; or CR vehicle/negative control). The animals were sacrificed 6 weeks later, and tumor number, size, plasma hormone levels, and the weight of estrogen-sensitive organs were analyzed. In contrast to mestranol treatment, CR treatment did not stimulate cancerous growth. There were no significant differences in tumor number or size between the CR groups and the vehicle control. Likewise, prolactin, follicle-stimulating hormone, and luteinizing hormone levels and organ weights and endometrial proliferation were unaffected. The lack of mammary tumor-stimulating effects of this extract is of great significance in establishing the safety of CR extracts for treatment of menopausal symptoms in women with a history of breast cancer in which hormone-replacement therapy is contraindicated. |
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Title:
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Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. |
| Author(s): |
Singh NP, Lai H. |
| Artemisinin becomes cytotoxic in the presence of ferrous iron. Since iron influx is high in cancer cells, artemisinin and its analogs selectively kill cancer cells under conditions that increase intracellular iron concentrations. We report here that after incubation with holotransferrin, which increases the concentration of ferrous iron in cancer cells, dihydroartemisinin, an analog of artemisinin, effectively killed a type of radiation-resistant human breast cancer cell in vitro. The same treatment had considerably less effect on normal human breast cells. Since it is relatively easy to increase the iron content inside cancer cells in vivo, administration of artemisinin-like drugs and intracellular iron-enhancing compounds may be a simple, effective, and economical treatment for cancer. |
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Title:
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The role of Thomsen-Friedenreich antigen in adhesion of human breast and prostate cancer cells to the endothelium. |
| Author(s): |
Glinsky VV, Glinsky GV, Rittenhouse-Olson K, Huflejt ME, Glinskii OV, Deutscher SL, Quinn TP. |
| Interactions of metastatic cancer cells with vasculatory endothelium are critical during early stages of cancer metastasis. Understanding the molecular underpinnings of these interactions is essential for the development of new efficacious cancer therapies. Here we demonstrate that cancer-associated carbohydrate T antigen plays a leading role in docking breast and prostate cancer cells onto endothelium by specifically interacting with endothelium-expressed beta-galactoside-binding protein, galectin-3. Importantly, T antigen-bearing glycoproteins are also capable of mobilizing galectin-3 to the surface of endothelial cells, thus priming them for harboring metastatic cancer cells. The T antigen-mediated, tumor-endothelial cell interactions could be efficiently disrupted using synthetic compounds either mimicking or masking this carbohydrate structure. High efficiency of T antigen-mimicking and T antigen-masking inhibitors of tumor cell adhesion warrants their further development into antiadhesive cancer therapeutics. |
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Title:
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Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. |
| Author(s): |
Jacobson JS, Troxel AB, Evans J, Klaus L, Vahdat L, Kinne D, Lo KM, Moore A, Rosenman PJ, Kaufman EL, Neugut AI, Grann VR. |
| PURPOSE: Most breast cancer survivors experience hot flashes; many use complementary or alternative remedies for these symptoms. We undertook a randomized clinical trial of black cohosh, a widely used herbal remedy for menopausal symptoms, among breast cancer patients. PATIENTS AND METHODS: Patients diagnosed with breast cancer who had completed their primary treatment were randomly assigned to black cohosh or placebo, stratified on tamoxifen use. At enrollment, patients completed a questionnaire about demographic factors and menopausal symptoms. Before starting to take the pills and at 30 and 60 days, they completed a 4-day hot flash diary. At the final visit, they completed another menopausal symptom questionnaire. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured in a subset of patients at the first and final visits. RESULTS: Of 85 patients (59 on tamoxifen, 26 not on tamoxifen) enrolled in the study, 42 were assigned to treatment and 43 were assigned to placebo; 69 completed all three hot flash diaries. Both treatment and placebo groups reported declines in number and intensity of hot flashes; the differences between the groups were not statistically significant. Both groups also reported improvements in menopausal symptoms that were, for the most part, not significantly different. Changes in blood levels of FSH and LH also did not differ in the two groups. CONCLUSION: Black cohosh was not significantly more efficacious than placebo against most menopausal symptoms, including number and intensity of hot flashes. Our study illustrates the feasibility and value of standard clinical trial methodology in assessing the efficacy and safety of herbal agents. |
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Title:
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Growth inhibition of human breast cancer cells by herbs and phytoestrogens. |
| Author(s): |
Dixon-Shanies D, Shaikh N. |
| Epidemiologic studies have suggested that consumption of phytoestrogen-rich foods may protect against breast cancer, and phytoestrogens such as genistein have been reported to both inhibit and stimulate the growth of some human breast cancer cells. The phytoestrogens genistein, daidzein, biochanin A, and coumestrol were tested and found to inhibit serum-stimulated growth in both T-47D and MCF-7 breast cancer cells at 10-100 microM. Extracts of several estrogenic herbs, including hops, black cohosh and vitex, inhibited growth of T-47D cells. These in vitro results suggest that certain herbs and phytoestrogens may have potential in the prevention of breast cancer. |
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