The beneficial effects of soy are more convincing if soy has been consumed throughout life rather than if the intake starts at menopause (114, 115). Data from wk 11 of treatment is presented. As discussed above, Wnt/-catenin is one of the pathways affected by genistein/soy (93, 94) and, therefore, early-life exposure to soy may affect later breast cancer risk by altering gene expression epigenetically in a manner that affects mammary epithelial cell proliferation and differentiation. Hedlund TE, van Bokhoven A, Johannes WU, Nordeen SK, Ogden LG. Figure reproduced with permission from (41). Chang EC, Charn TH, Park SH, Helferich WG, Komm B, Katzenellenbogen JA, Katzenellenbogen BS. official website and that any information you provide is encrypted 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. 5, Phytoestrogen and breast cancer prevention. Because differentiation of mammary epithelial structures is closely related to breast cancer risk (98), it is possible that the protective effect of childhood and adolescent soy consumption on mammary gland morphology is epigenetically induced. government site. Mazur W, Fotsis T, Wahala K, Ojala S, Salakka A, Adlercreutz H. Isotope dilution gas chromatographic-mass spectrometric method for the determination of isoflavonoids, coumestrol, and lignans in food samples. Sotgia F, Williams TM, Cohen AW, Minetti C, Pestell RG, Lisanti MP. Bethesda, MD 20894, Web Policies
Soy consumption and histopathologic markers in breast tissue using tissue microarrays. The use of a nonhuman primate animal model is critical in reproductive biology, because the endometrial and ovarian physiologies of monkeys are almost identical to that of women (45). 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. However, genistein also can reactivate genes by promoter demethylation and active histone modification (103). Genistein also has been reported to downregulate Her2 in human breast cancer cells (79). These doses parallel those observed in Asians. Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL. An official website of the United States government. Maskarinec G, Erber E, Verheus M, Hernandez BY, Killeen J, Cashin S, Cline JM. Dietary genistin stimulates growth of estrogen-dependent breast cancer tumors similar to that observed with genistein. In contrast, the study done in Chinese women found a significantly reduced risk of recurrence in women having the highest level of isoflavones and soy protein in their diet. 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). None of these studies, even those from the same authors, used similar amounts of isoflavones or foods. BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. Guest Editor Disclosure: Neil Shay declares no conflict of interest. However, this study showed that women who consumed soy both during early life and adulthood had a significantly reduced risk of breast cancer (Table 2). Messina M, McCaskill-Stevens W, Lampe JW. It is puzzling why the data obtained using well-established breast cancer models that are used widely among investigators and findings in the 2 recent human studies are in stark contrast with each other. Cardiovascular and renal benefits of dry bean and soybean intake, Soy protein, isoflavones and cardiovascular disease risk, Genistein appears to prevent early postmenopausal bone loss as effectively as hormone replacement therapy. Cells (1.5 105 MCF-7 cells/site) were injected subcutaneously into dorsal flanks of ovariectomized athymic mice. 8600 Rockville Pike The mean follow-up time for these women was 6.31 y. This publication must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact. One study conducted in Asian women did not find any protective effect by adolescent soy intake and breast cancer risk (69). wrote the paper and L.H-C. had primary responsibility for the final content. 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. McMichael-Phillips DF, Harding C, Morton M, Robert SA, Howell A, Potten CS, Bundred NJ. Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice. Thus, these studies used food sources that greatly differ in the amount and profile of isoflavones and other bioactive component factors that dictate final bioaccesibility and bioavailability of isoflavones. It is not known whether prepubertal genistein exposure might increase or reduce methylation patterns. Before In addition, we (S. de Assis, A. Warri, L. Hilakivi-Clarke, unpublished data) and others (72) have shown in mice and humans that prepubertal genistein exposure (mice) and soy intake (humans) reduces Her2 expression in mammary tumors.
Accessibility 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. 2). Chromatin remodeling factor Pygo2 epigenetically regulates transcriptional activation of -catenin downstream of Wnt signaling (99). The Isoflavones are known to accumulate in many plant species at various concentrations. For example, consumption is significantly different even in Chinese Americans (4 g/d) compared with their counterparts from China (36 g/d) (8). Food matrix modulates the estrogenic effects of equivalent amounts of genistein aglycone (750 g/g) on estrogen-dependent MCF-7 tumor growth in athymic mice. (44) reported that consumption of whole soy activated estrogen response element (ERE) in the mammary glands of luciferase transgenic mice. National Library of Medicine Caveolin-1-deficient mice have an increased mammary stem cell population with upregulation of Wnt/. The findings of this study indicated that soy intake was associated with reduced breast cancer risk among women living in the West. Although they developed breast cancer despite soy intake, the tumors may differ among the high and low soy consumers. Shajahan A, Goel S, de Assis S, Yu B, Clarke R, Hilakivi-Clarke L. Changes in mammary caveolin-1 signaling pathways are associated with breast cancer risk in rats exposed to estradiol, Hormone Molecular Biology and Clinical Investigation. (61) concluded the opposite, i.e. Most Asian soy products use whole soybeans with or without fermentation. Dietary legumes such as black beans, lentils, lima beans, Mung beans, and soybeans are sources of a variety of isoflavones, but only the soybeans are a primary source of genistein in human diet (4, 5). In the study by Maskarinec et al. We propose that the reduction in risk involves epigenetic changes that result in alterations in the expression of genes that regulate mammary epithelial cell fate, i.e. Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice. However, among Asian women living in Asia, high soy consumption did not significantly reduce the risk of developing breast cancer [odds ratio (OR) = 0.89; 95% CI 0.711.12]. Thus, dietary intake of whole soy activates estrogenic pathways in a mouse mammary gland. 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. Lavigne et al. Because Asian American women consume significantly less soy foods than Asian women, it is reasonable to assume that soy protects Asians from developing breast cancer. Two meta-analyses have been performed that investigated the effect of soy on breast cancer risk. 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. They found that genistein affected Wnt and Notch signaling, indicating an effect on stem cell behavior, i.e. HHS Vulnerability Disclosure, Help 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. Further, hyperactive Wnt/-catenin signaling leads to dysregulation of mammary stem cell behavior (91), which may be the cornerstone of cancer susceptibility and growth. Estrogenic effects of genistein on the growth of estrogen receptor -positive human breast cancer (MCF-7) cells in vitro and in vivo. One likely explanation for the survival benefit in Chinese women consuming high levels of soy is that they probably consumed soy throughout the life. Soy protein and isoflavone intakes were assessed from FFQ and by interview. Although genistein binds more strongly to ER than to ER (33), physiological doses of genistein activate ER equally well as E2 does (34). Genistein affects HER2 protein concentration, activation, and promoter regulation in BT-474 human breast cancer cells. Presented at the conference, Soy Summit: Exploration of the Nutrition and Health Effects of Whole Soy, held in New York, NY, September 2122, 2009. 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. The increase in E2-induced proliferation requires that ER activates amphiregulin, which then binds to epidermal growth factor receptor (EGFR); activation of EGFR by amphiregulin leads to mammary epithelial proliferation (75). A meta-analysis published 2 y later by Wu et al. Learn more Our unpublished data indicate that pubertal genistein exposure causes a persistent upregulation of caveolin-1, also a tumor suppressor regulated by estrogens (82). Sotoca AM, Ratman D, van der Saag P, Strom A, Gustafsson JA, Vervoort J, Rietjens IM, Murk AJ. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Both the negative control (NC) and PC mice were fed a low-phytoestrogen control diet (AIN-93G). The .gov means its official. Lavigne JA, Takahashi Y, Chandramouli GV, Liu H, Perkins SN, Hursting SD, Wang TT. For these reasons, estrogens present in our food and environment may pose a risk to humans. Gallo D, Ferlini C, Fabrizi M, Prislei S, Scambia G. Lack of stimulatory activity of a phytoestrogen-containing soy extract on the growth of breast cancer tumors in mice. The difference in function between the 2 ER remains to be established, but it is generally assumed that ER mediates the proliferative actions of estrogens and ER binds to ER and inhibits its action (3032). Reproduced with permission. 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. Majid S, Dar AA, Shahryari V, Hirata H, Ahmad A, Saini S, Tanaka Y, Dahiya AV, Dahiya R. Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-cell translocation gene 3 in prostate cancer. Although genistein has been reported to upregulate several tumor suppressor genes and downregulate oncogenes, it is not known whether there is a causal relationship between these transcriptional changes and reduced tumorigenesis. Shu XO, Jin F, Dai Q, Wen W, Potter JD, Kushi LH, Ruan Z, Gao YT, Zheng W. Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. However, when the exposure occurred during early development, blood testosterone levels and development of the testis were affected (49). Su Y, Eason RR, Geng Y, Till SR, Badger TM, Simmen RC. Positive control (+E2) mice were reimplanted with a new E2 pellet and along with negative controls (E2) were fed an AIN 93G diet alone. However, this study only determined whether ERE was activated; it did not assess changes in mammary cell proliferation or any other functional endpoints. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of The Journal of Nutrition. that no protective effect was seen in Western women who consumed either no or low levels of soy products, most of which are not traditional soy foods, but a significant reduction was seen in Asian women and Asian American women [OR = 0.71; 95% CI 0.600.85]. This idea has been challenged by the apparent estrogenicity of soy isoflavones, particularly genistein. 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). In 2 of these studies, both conducted in Asian women living either in Asia (66) or the US (67), the risk was one-half of that in the comparison group (lowest soy intake quartile). The Guest Editor for this supplement is Neil Shay.
Wu AH, Ziegler RG, Nomura AMY, West DW, Kolonel LN, Horn-Ross PL, Hoover RN, Pike MC. 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. 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. 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. Western soy products prepared using isoflavone supplements can contain several-fold higher levels of, e.g., genistein and therefore may have estrogenic effects. Studies that have explored the effect of consumption of isoflavones alone or in soy foods on high mammographic density, a strong marker of increased breast cancer risk (56), have found no effect (5759). Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W. Soy food intake and breast cancer survival. 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). After tumor establishment, E2 pellets were removed and mice were randomly assigned to treatment groups. 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. In a subsequent study, Su et al. Phytoestrogen-mediated inhibition of proliferation of the human T47D breast cancer cells depends on the ER. One study found that soy increased expression of pS2, suggesting an estrogenic effect on the breast (55). (50) suggested that soy intake reduces circulating estrogen levels, several subsequent studies have not found any marked differences (51, 52).
More research is needed to understand why soy intake during early life may both reduce breast cancer risk and risk of recurrence. 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. Tamoxifen users who consumed the highest level of soy products exhibited no increase in the risk of recurrence, but nonusers did. In humans, the estrogenic effects of isoflavones alone or in soy foods have been investigated in numerous studies with conflicting outcomes. Epigenetic regulation of gene expression has been identified as the key process allowing the environment during embryonic development to interact with the genotype, resulting in the observed phenotype (95, 96). cell proliferation and differentiation. Federal government websites often end in .gov or .mil.
puberty and pregnancy. Five case-control studies have investigated whether soy intake during childhood or adolescence affects later breast cancer risk. Estrogen receptor positive proliferating cells in the normal and precancerous breast, Amphiregulin is an essential mediator of estrogen receptor, Evaluation of the biochemical targets of genistein in tumor cells. Chandrareddy A, Muneyyirci-Delale O, McFarlane SI, Murad OM. 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. Fan S, Meng Q, Auborn K, Carter T, Rosen EM. The protective effect occurred in both women diagnosed with ER+ or ER breast tumors and in tamoxifen users and nonusers. For phytoestrogen groups, mice consumed either dietary genistin (1200 g/g) or genistein (750 g/g) mixed with AIN 93G.
Some of these studies indicate that soy protein isolate increases the volume of breast fluid (marker of increased breast cancer risk), presence of hyperplastic epithelial cells, and cell proliferation (53, 54). Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, Rowlands T, Egeblad M, Cowin P, et al. We also review the literature regarding potential risks genistein poses for breast cancer survivors. Wu AH, Wan P, Hankin J, Tseng CC, Yu MC, Pike MC. Erdman JW, Jr, Badger TM, Lampe JW, Setchell KD, Messina M. Not all soy products are created equal: caution needed in interpretation of research results. 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. When Asian women immigrate to the West, their daughters who were born in the West have higher risk than the mothers and granddaughters risk is similar to that of Caucasian women (20). This is a significant change, because glycitein highly accumulates in soy germ, providing a unique isoflavone profile that no other traditional or Westernized soy food has. Although 2 recent human studies in breast cancer survivors did not indicate adverse effects (106, 107) and suggest a reduction in the risk of recurrence in Asian women consuming soy regularly, more studies are needed to determine whether Western soy products or isoflavone supplements are safe for women diagnosed with breast cancer. Differential ligand activation of estrogen receptors ER. Adolescent and adult soy food intake and breast cancer risk: results from the Shanghai Women's Health Study. Genistein is a potent tyrosine kinase inhibitor (76) and therefore may prevent E2-induced cell proliferation. The study by Shu et al. 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. sharing sensitive information, make sure youre on a federal Using a 750-mg/kg diet dose, Allred et al. Many of these contain several-fold more isoflavones than traditional Asian soy products (6). After tumor establishment (40 mm2), E2 pellets were removed and mice were randomly assigned to 4 treatment groups. The soy isoflavone genistein promotes apoptosis in mammary epithelial cells by inducing the tumor suppressor PTEN. Sharpe RM, Martin B, Morris K, Greig I, McKinnell C, McNeilly AS, Walker M. Infant feeding with soy formula milk: effects on the testis and on blood testosterone levels in marmoset monkeys during the period of neonatal testicular activity. Westernized soy products are quite different from those consumed in the traditional Asian diet. Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention. OR and 95% CI of breast cancer risk in women consuming different levels of soy during childhood/adolescence and adult life1. The supplement coordinators for this supplement are Sharon R. Akabas, Columbia University, and Connie M. Weaver, Purdue University. Equivalent amounts of dietary genistin and genistein (750 g/g) stimulate growth of estrogen-dependent breast cancer tumors MCF-7 in 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. If mice were fed <125 mg/kg diet of genistein or genistein was administered via subcutaneous injections, the stimulatory effect was not seen (26, 42, 43). Deficiency of Pten accelerates mammary oncogenesis in MMTV-Wnt-1 transgenic mice. Connie M. Weaver serves on Pharmavites Advisory Board. Genistein alters methylation patterns in mice, Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. 2Supported by the National Cancer Institute (U54 {"type":"entrez-nucleotide","attrs":{"text":"CA000970","term_id":"24277952","term_text":"CA000970"}}CA000970 to L.H-C.), the National Institute on Aging (P01 AG024387 to W.G.H. Adverse effects of phytoestrogens on reproductive health: a report of three cases. We and others have shown that prepubertal genistein exposure increases the differentiation of the mammary epithelial tree (64). A study done in 1954 female breast cancer survivors in the US determined their genistein, daidzein, and glycitein intake using the Fred Hutchinson Cancer Research Center FFQ and asking survivors about their use of herbal supplements and herbs (106). In these studies, intact or ovariectomized cynomolgus monkeys were fed a control diet or a diet containing soy or isoflavones (46, 47). Positive control (PC) mice were reimplanted with a new E2 pellet. This is because proliferating mammary cells do not express ER (73); only proliferating mammary tumor cells do (74). Arendt LM, Rudnick JA, Keller PJ, Kuperwasser C. Variations in isoflavone levels in soy foods and soy protein isolates and issues related to isoflavone databases and food labeling, Comprehensive phytochemical profile of soy protein isolate. Pei RJ, Sato M, Yuri T, Danbara N, Nikaido Y, Tsubura A. A diverse array of soybean foods and derivates is widely available in Western diets, such as oil, meal, flour, protein isolates, and dairy and meat substitutes, including milk, yogurt, ice cream, cheese, sausages, and veggie burgers. Risk of recurrence of breast cancer by soy intake, assessed using FFQ, among 1954 Western breast cancer survivors (101) (A) and 5042 Chinese breast cancer survivors (102) (B). The https:// ensures that you are connecting to the 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. 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. Only at very low genistein concentrations (58 nmol/L; in comparison, genistein concentrations in Asian women are 1000 nmol/L) does this isoflavone potentially act through ER rather than ER (34). In contrast, another study by Maskarinec et al. The study also addressed whether soy intake affected the risk of recurrence among women using tamoxifen, because animal studies have indicated that genistein prevents tamoxifen action in MCF-7 human breast cancer cells in vitro or in vivo (106).