(61). IARC Cancer Base no. Publication costs for this supplement were defrayed in part by the payment of page charges. Day JK, Bauer AM, DesBordes C, Zhuang Y, Kim BE, Newton LG, Nehra V, Forsee KM, MacDonald RS, et al. proliferation and differentiation. Guha N, Kwan ML, Quesenberry CP, Jr, Weltzien EK, Castillo AL, Caan BJ. Despite the vast variety of soy foods in the Western markets, soy food consumption is still low, except in cases where dietary habits can lead to exceptionally high exposure to soy and isoflavones (7). Further, maternal genistein exposure negates the DNA hypomethylating effect of an endocrine disruptor, bisphenol A (102). Maskarinec G, Takata Y, Franke AA, Williams AE, Murphy SP. Using a 750-mg/kg diet dose, Allred et al. Various doses of soy isoflavones do not modify mammographic density in postmenopausal women. Tumors were monitored weekly and tumor size was calculated and is expressed as mean cross sectional area (mm2) of all tumors in each treatment group SEM.

3). Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W. Soy food intake and breast cancer survival. Dave B, Eason RR, Till SR, Geng Y, Velarde MC, Badger TM, Simmen RC. One likely explanation for the survival benefit in Chinese women consuming high levels of soy is that they probably consumed soy throughout the life. Tamoxifen users who consumed the highest level of soy products exhibited no increase in the risk of recurrence, but nonusers did. Concentration-dependent effects of genistein on global gene expression in MCF-7 breast cancer cells: an oligo microarray study, Expression profiling of rat mammary epithelial cells reveals candidate signaling pathways in dietary protection from mammary tumors, Soy isoflavone genistein upregulates epithelial adhesion molecule E-cadherin expression and attenuates, Epigenetic regulation in mammalian preimplantation embryo development, Environmental epigenomics and disease susceptibility, DNA methylation control of tissue polarity and cellular differentiation in the mammary epithelium. All authors read and approved the final manuscript. official website and that any information you provide is encrypted

Amphiregulin is a tyrosine kinase, as are EGF, transforming growth factors, and others, which in addition to EGFR bind to other members of tyrosine kinase receptor family, such as human epidermal growth factor receptor 2 (Her2). They found that genistein affected Wnt and Notch signaling, indicating an effect on stem cell behavior, i.e. Western soy products prepared using isoflavone supplements can contain several-fold higher levels of, e.g., genistein and therefore may have estrogenic effects. Anderson JJ, Anthony MS, Cline JM, Washburn SA, Garner SC. Results reviewed here suggest that women consuming moderate amounts of soy throughout their life have lower breast cancer risk than women who do not consume soy; however, this protective effect may originate from soy intake early in life. Soy intake and risk of breast cancer in Asians and Asian Americans. The actions of genistein through the 2 ER also depend on the developmental stage of the breast: ER is expressed at a significantly higher level than ER during early development and in normal adult breast, while in the breast tumor, ER expression is higher than ER expression (35). In 2009, 2 human studies were published that investigated the recurrence and metastasis of breast cancer in relation to soy intake or circulating isoflavone levels after diagnosis. The mechanisms explaining the breast cancer risk-reducing effect of early soy intake or the protective effect in Asian breast cancer survivors remain to be established. Ziegler RG, Hoover RN, Pike MC, Hildesheim A, Nomura AMY, West DW, Wu-Williams AH, Kolonel LN, Horn-Ross PL, et al. Lu L-JW, Anderson KE, Grady JJ, Nagamani M. Effects of soya consumption for one month on steroid hormones in premenopausal women: implications for breast cancer risk reduction, Hormonal effects of soy isoflavones: studies in premenopausal and postmenopausal women. Bethesda, MD 20894, Web Policies (93) isolated mammary epithelial cells from the glands of rats fed a diet containing no isoflavones, soy protein isolate, or genistein throughout the fetal period until killing on postnatal d 50 and performed gene microarrays. Effect of prenatal and prepubertal genistein exposure on N-methyl-N-nitrosourea-induced mammary tumorigenesis in female Sprague-Dawley rats. Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner. Treatment groups also included an AIN-93G diet with genistein (GI), mixed isoflavones (MI), Novasoy (NS), molasses (MOL), and soy flour + mixed isoflavones (SF + MI). (107) included 5042 Chinese breast cancer survivors diagnosed between 2002 and 2006 and followed for 3.9 y on average. The concern about soys ability to promote breast cancer growth is heightened by our findings (40, 104) obtained in MCF-7 human breast cancer cells in vitro and in vivo. Ju YH, Doerge DR, Allred KF, Allred CD, Helferich WG. Most studies conducted using adult animals do not support an association between an exposure to genistein and mammary tumorigenesis (62, 63). 12 servings/d of traditional Asian soy products. Careers, {"type":"entrez-nucleotide","attrs":{"text":"CA000970","term_id":"24277952","term_text":"CA000970"}}, Phytoestrogens and breast cancer: a complex story, Mammary developmental fate and breast cancer risk, Endogenous and exogenous hormonal factors, High-performance liquid chromatographic assay of isoflavonoids and coumestrol from human urine. Wu AH, Ziegler RG, Nomura AMY, West DW, Kolonel LN, Horn-Ross PL, Hoover RN, Pike MC. Ju YH, Allred CD, Allred KF, Karko KL, Doerge DR, Helferich WG. In humans, the estrogenic effects of isoflavones alone or in soy foods have been investigated in numerous studies with conflicting outcomes. (60) and included 18 studies. Cells (1.5 105 MCF-7 cells/site) were injected subcutaneously into dorsal flanks of ovariectomized athymic mice. 4Lombardi Comprehensive Cancer Center Georgetown University, Washington, DC 20057, 5Department of Oncology, Georgetown University, Washington, DC 20057, 6Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, IL 61801. Estrogenic effects of genistein on the growth of estrogen receptor -positive human breast cancer (MCF-7) cells in vitro and in vivo. (60) and in the Asian category by Wu et al. Differential ligand activation of estrogen receptors ER. The mechanisms responsible for persistent changes in gene expression in the mammary glands of individuals exposed to genistein or other (estrogenic) compounds before onset of puberty may involve epigenetic modifications. Additionally, the reduction in risk may be seen only if soy is consumed throughout life or during periods before or during extensive development of the breast, i.e. Genistein alters methylation patterns in mice, Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Cabanes A, Wang M, Olivo S, de Assis S, Gustafsson JA, Khan G, Hilakivi-Clarke L. Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis. Because estrogens increase breast cancer risk and genistein promotes the growth of ER-positive human breast cancer cells, it has remained unclear whether this isoflavone or soy is safe. 1Published in a supplement to The Journal of Nutrition. This is because proliferating mammary cells do not express ER (73); only proliferating mammary tumor cells do (74). Learn more (57), the nutritional intervention consisted of a choice of 2 daily servings of soy. Sacks FM, Lichtenstein A, Van Horn L, Harris W, Kris-Etherton P, Winston M. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee, Cancer incidence, mortality and prevalence worldwide. Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast, Two-week soy supplementation has an estrogenic effect on normal premenopausal breast. The reduction in risk was strongest among premenopausal women. For phytoestrogen groups, mice consumed either dietary genistin (1200 g/g) or genistein (750 g/g) mixed with AIN 93G. The study done in Western women showed no protective effect and an almost significantly increased risk of recurrence among those not taking tamoxifen and having the highest intake of genistein and daidzein. Ovarian estrogens, adipose-derived estrogens, and estrogenic compounds, e.g. 2). When the effects of soy consumption on intact mouse mammary gland were explored, it was found that genistein in the context of whole soy acts as an estrogen. Further, hyperactive Wnt/-catenin signaling leads to dysregulation of mammary stem cell behavior (91), which may be the cornerstone of cancer susceptibility and growth. Maternal genistein alters coat color and protects avy mouse offspring from obesity by modifying the fetal epigenome. More research is needed to understand why soy intake during early life may both reduce breast cancer risk and risk of recurrence. Together, these findings suggest that a protective effect is seen among Asian American women who continue consuming moderate levels of soy on a daily basis compared with Asian American women who adopt Western dietary habits. It can be concluded that consumption of soy foods or intake of soy isoflavones remains in the spotlight as a possible treatment to reduce menopausal symptoms and prevent bone loss. For example, Wnt/-catenin signaling regulates progenitor cells; overactivity of this pathway leads to excessive mammary outgrowth (90, 91). Genistein affects HER2 protein concentration, activation, and promoter regulation in BT-474 human breast cancer cells. Caveolin-1-deficient mice have an increased mammary stem cell population with upregulation of Wnt/. Soybeans and soy foods contain several compounds with the putative ability to inhibit carcinogenesis, including protease inhibitors (21), phytates (22, 23), and isoflavones (2428). Accessibility In rats and mice, pubertal exposure to genistein causes a persistent upregulation of both ER and ER, whereas E2 downregulates ER and upregulates ER in the mammary gland (70, 71). Sotgia F, Williams TM, Cohen AW, Minetti C, Pestell RG, Lisanti MP. Wu AH, Wan P, Hankin J, Tseng CC, Yu MC, Pike MC. Breast differentiation and its implication in cancer prevention. For example, consumption is significantly different even in Chinese Americans (4 g/d) compared with their counterparts from China (36 g/d) (8). doom Su Y, Eason RR, Geng Y, Till SR, Badger TM, Simmen RC. These investigators also observed that the combination of high exogenous E2 and high dietary isoflavones reduced circulating (47) and intra-breast (48) E2 concentrations in monkeys. Most of the rise in popularity of soy products, and lately of dietary supplements containing soy isoflavones, has come from their portrayal as the panacea for a variety of health ailments from relieving postmenopausal symptoms (9, 10) to the prevention of cardiovascular disease (11, 12) and osteoporosis (13, 14). However, other lifestyle factors, such as degree of physical activity, could be important contributors to explain a populations disparities of breast cancer incidence (19). Additional evidence for genistein binding and activating ER in breast tumors is that it activates a number of estrogen-responsive genes, including pS2 and c-fos, in ER+ breast cancer cell lines in culture (3638). In addition to changes in ER, genistein affects the expression of many transcription factors that are directly or indirectly regulated by ER, including tumor suppressor genes BRCA1 (70, 80) and PTEN (81), both in vitro and vivo at physiological concentrations of this isoflavone. Genistein in soy activates estrogen receptor (ER)- and ER and acts as an estradiol in multiple target tissues. Wood CE, Appt SE, Clarkson TB, Franke AA, Lees CJ, Doerge DR, Cline JM. Guest Editor Disclosure: Neil Shay declares no conflict of interest. A 2-year soy intervention in premenopausal women does not change mammographic densities. Effects of high-dose soy isoflavones and equol on reproductive tissues in female cynomolgus monkeys, Effects of soy on the mammary glands of premenopausal female monkeys, Soy isoflavonoid effects on endogenous estrogen metabolism in postmenopausal female monkeys. In humans, lifetime exposure to high estrogen levels is associated with increased breast cancer risk (3). Tumors were monitored weekly and tumor size was calculated and is expressed as mean cross sectional area (mm2) of all tumors in each treatment group SEM. Mardon J, Mathey J, Kati-Coulibaly S, Puel C, Davicco MJ, Lebecque P, Horcajada MN, Coxam V. Influence of lifelong soy isoflavones consumption on bone mass in the rat, Effect of neonatal exposure to genistein on bone metabolism in mice at adulthood. This is supported by findings in numerous studies showing that exposure to genistein during the prepubertal period inhibits mammary epithelial cell proliferation (77, 78). Because genistein acts through activation of ER and ER, it is not surprising that prepubertal genistein exposure causes a long-lasting change in the expression of the ER. Petrakis NL, Barnes S, King EB, Lowenstein J, Wiencke J, Lee MM, Miike R, Kirk M, Coward L. Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women. (72) found that breast tumors in women who consumed soy early in life expressed lower levels of HER2/neu protein and had reduced PCNA staining compared with tumors in women consuming low levels of soy. However, when the exposure occurred during early development, blood testosterone levels and development of the testis were affected (49). Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. These findings suggest that although adult exposure to genistein does not elicit functional changes in the reproductive system or mammary gland of nonhuman primates, early-life exposure may have adverse effects. Thus, these women are able to maintain the low breast cancer risk of Asian countries if they continue consuming soy, but if their diet becomes Westernized, these women exhibit the same high risk as Caucasian women do. We and others have shown that prepubertal genistein exposure increases the differentiation of the mammary epithelial tree (64). The conference was organized by the Institute of Human Nutrition, Columbia University, through an unrestricted educational grant from Pharmavite, LLC. In conclusion, the breast cancer studies discussed in this review mostly have been done using genistein. Findings obtained in 2 recent human studies show that a moderate consumption of diet containing this isoflavone does not increase the risk of breast cancer recurrence in Western women, and Asian breast cancer survivors exhibit better prognosis if they continue consuming a soy diet. The reason why a protective effect is not seen in Asian countries may be related to the fact that everybody consumes soy and even the lowest level of intake, which corresponds to high intake in Western countries, is enough soy to reduce the risk. A meta-analysis published 2 y later by Wu et al. Women who had never taken tamoxifen but were estimated to have the highest intake of daidzein [HR = 2.40 (95% CI 0.936.18)] or genistein [HR = 2.42 (95% CI 0.956.21)] exhibited an almost significant increase in risk of recurrence. The In addition, no evidence of estrogenic effects on the mammary gland were observed, indicating that dietary soy isoflavones do not have estrogenic effects on the uterus or mammary gland. Allred et al. The only study involving Caucasian women showed the lowest, but still significant, reduction in risk (68). Although soy intake may not have affected their risk of developing breast cancer (60), these results provide powerful evidence in support of soy reducing the risk of recurrence among women who have consumed soy throughout their life. This idea has been challenged by the apparent estrogenicity of soy isoflavones, particularly genistein. No evidence of an association between risk of recurrence and intake of genistein [HR = 0.95 (95% CI 0.521.75)] or daidzein [HR = 0.96 (95% CI 0.521.76)] was found, but high glycitein intake was nonsignificantly associated with reduced risk (P-trend < 0.10) (Fig. Messina M, McCaskill-Stevens W, Lampe JW. Specifically, maternal exposure to genistein increases methylation of 6 cytosine-guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene at the viable yellow Agouti mice (100), increasing the number of Agouti offspring that exhibit the pseudo agouti phenotype linked to lowered cancer risk. A study by Korde et al. The https:// ensures that you are connecting to the Allred CD, Allred KF, Ju YH, Goeppinger TS, Doerge DR, Helferich WG. menopause soybean estrogenic stimulates aguaje

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