Soy for breast cancer survivors: a critical review of the literature.

A variety of health benefits, including protection against breast cancer, have been attributed to soy food consumption, primarily because of the soybean isoflavones (genistein, daidzein, glycitein). Isoflavones are considered to be possible selective estrogen receptor modulators but possess nonhormonal properties that also may contribute to their effects. Concern has arisen over a possible detrimental effect of soy in breast cancer patients because of the estrogen-like effects of isoflavones. Genistein exhibits a biphasic effect on the growth of MCF-7 cells in vitro, stimulating proliferation at low concentrations but inhibiting it at high concentrations. In ovariectomized athymic mice implanted with MCF-7 cells, both genistein and soy protein stimulate tumor growth in a dose-dependent manner. In contrast, in intact mice fed estrogen, genistein inhibits tumor growth. Although two studies in premenopausal women suggested that soy exerts estrogenic-like effects on breast tissue, recently conducted year-long studies indicated that isoflavone supplements do not affect breast tissue density in premenopausal women and may decrease density in postmenopausal women. These latter effects are opposite to those of hormone replacement therapy (HRT). Importantly, substantial data suggest that the progestogen, not the estrogen, component of HRT increases risk of developing breast cancer. Furthermore, recently conducted studies have failed to find that even HRT reduces survival in breast cancer patients. Overall, the data are not impressive that the adult consumption of soy affects the risk of developing breast cancer or that soy consumption affects the survival of breast cancer patients. Consequently, if breast cancer patients enjoy soy products, it seems reasonable for them to continue to use them.

[1]  A. Conney,et al.  Functional role of estrogen metabolism in target cells: review and perspectives. , 1998, Carcinogenesis.

[2]  D. Alekel,et al.  Soy Protein, Soybean Isoflavones, and Bone Health: A Review of the Animal and Human Data , 2000 .

[3]  R. Fuchs-Young,et al.  Estrogen receptor activation via activation function 2 predicts agonism of xenoestrogens in normal and neoplastic cells of the uterine myometrium. , 1999, Cancer research.

[4]  D. Ingram,et al.  Case-control study of phyto-oestrogens and breast cancer , 1997, The Lancet.

[5]  B. Psaty,et al.  Duration of estrogen replacement therapy in relation to the risk of incident myocardial infarction in postmenopausal women. , 1997, Archives of internal medicine.

[6]  W. Blair,et al.  Soy and experimental cancer: animal studies. , 1995, The Journal of nutrition.

[7]  C. Weinberg,et al.  Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women. , 1995, The Journal of clinical endocrinology and metabolism.

[8]  Martin J. Yaffe,et al.  Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention , 2001, Current oncology reports.

[9]  L. Leung,et al.  Bcl-2 is not reduced in the death of MCF-7 cells at low genistein concentration. , 2000, The Journal of nutrition.

[10]  P. Goss,et al.  Estrogen and the risk of breast cancer. , 2001, The New England journal of medicine.

[11]  H. Ogawara,et al.  Use and specificity of genistein as inhibitor of protein-tyrosine kinases. , 1991, Methods in enzymology.

[12]  K. Anderson,et al.  Increased urinary excretion of 2-hydroxyestrone but not 16alpha-hydroxyestrone in premenopausal women during a soya diet containing isoflavones. , 2000, Cancer research.

[13]  D. Reid,et al.  The climacteric, osteoporosis and hormone replacement; views of women aged 45-49. , 1995, Maturitas.

[14]  Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. , 2000 .

[15]  S. Barnes,et al.  The role of soy products in reducing risk of cancer. , 1991, Journal of the National Cancer Institute.

[16]  N. Johnson,et al.  A comparison of complementary therapy use between breast cancer patients and patients with other primary tumor sites. , 2000, American journal of surgery.

[17]  M. Yamaguchi,et al.  Stimulatory effect of Daidzein in osteoblastic MC3T3-E1 cells. , 2000, Biochemical pharmacology.

[18]  E. Huberman,et al.  Genistein as an Inducer of Tumor Cell Differentiation: Possible Mechanisms of Action , 1995, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[19]  R. Prentice Future possibilities in the prevention of breast cancer: Fat and fiber and breast cancer research , 2000, Breast Cancer Research.

[20]  M. Faughnan,et al.  Phyto-oestrogens through the life cycle , 2000, Proceedings of the Nutrition Society.

[21]  L. Skoog,et al.  Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques. , 1996, American journal of obstetrics and gynecology.

[22]  W. Mazur,et al.  Pharmacokinetics of soybean isoflavones in plasma, urine and feces of men after ingestion of 60 g baked soybean powder (kinako). , 1998, The Journal of nutrition.

[23]  M. Juliana,et al.  Effect of miso (Japanese soybean paste) and NaCl on DMBA-induced rat mammary tumors. , 1990, Nutrition and cancer.

[24]  R. Yonemoto Breast cancer in Japan and United States: epidemiology, hormone receptors, pathology, and survival. , 1980, Archives of surgery.

[25]  J. Hodgson,et al.  Effects of isoflavonoids on blood pressure in subjects with high-normal ambulatory blood pressure levels: a randomized controlled trial. , 1999, American journal of hypertension.

[26]  K. Anderson,et al.  Decreased ovarian hormones during a soya diet: implications for breast cancer prevention. , 2000, Cancer research.

[27]  Herman Adlercreutz,et al.  In vitro bioassays of non-steroidal phytoestrogens , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[28]  W. Mazur,et al.  Phyto-oestrogens and Western diseases. , 1997, Annals of medicine.

[29]  J. Scimeca,et al.  Effect of intact and isoflavone-depleted soy protein on NMU-induced rat mammary tumorigenesis. , 2000, Carcinogenesis.

[30]  Y. Tonogai,et al.  Determination of the levels of isoflavonoids in soybeans and soy-derived foods and estimation of isoflavonoids in the Japanese daily intake. , 2000, Journal of AOAC International.

[31]  G A Colditz,et al.  Association of dietary intake of fat and fatty acids with risk of breast cancer. , 1999, JAMA.

[32]  J. Cline,et al.  Effects of mammalian and plant estrogens on mammary glands and uteri of macaques. , 1998, The American journal of clinical nutrition.

[33]  J. Tice,et al.  Phytoestrogens and healthy aging: gaps in knowledge: A workshop report , 2001, Menopause.

[34]  A. Franke,et al.  HPLC Analysis of Isoflavonoids and Other Phenolic Agents from Foods and from Human Fluids , 1998, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[35]  V. Beral,et al.  Soya foods and breast cancer risk: a prospective study in Hiroshima and Nagasaki, Japan , 1999, British Journal of Cancer.

[36]  K. Setchell,et al.  Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. , 1998, The American journal of clinical nutrition.

[37]  S. Affenito,et al.  Position of the American Dietetic Association and Dietitians of Canada: women's health and nutrition. , 1999, Journal of the American Dietetic Association.

[38]  Jun Wang,et al.  Dietary genistein: perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat. , 1998, Carcinogenesis.

[39]  P. Dannies,et al.  Antiestrogens are partial estrogen agonists for prolactin production in primary pituitary cultures , 1986, Molecular and Cellular Endocrinology.

[40]  C. Nagata,et al.  Effect of soymilk consumption on serum estrogen concentrations in premenopausal Japanese women. , 1998, Journal of the National Cancer Institute.

[41]  A. Maclennan,et al.  Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review. , 2001 .

[42]  J. Schenker,et al.  Short‐term Effects of Phytoestrogen‐rich Diet on Postmenopausal Women , 1997 .

[43]  Y. Nomura,et al.  Occurrence of breast cancer in relation to diet and reproductive history: a case-control study in Fukuoka, Japan. , 1985, National Cancer Institute monograph.

[44]  U. Mayr,et al.  Validation of two in vitro test systems for estrogenic activities with zearalenone, phytoestrogens and cereal extracts. , 1992, Toxicology.

[45]  G. Petroni,et al.  Risk of breast cancer with progestins in combination with estrogen as hormone replacement therapy. , 2001, The Journal of clinical endocrinology and metabolism.

[46]  S. Bingham,et al.  Daidzein and genistein contents of vegetables , 2000, British Journal of Nutrition.

[47]  C. Tsukamoto,et al.  Factors affecting isoflavone content in soybean seeds: changes in isoflavones, saponins, and composition of fatty acids at different temperatures during seed development , 1995 .

[48]  N. Petrakis,et al.  Nipple aspirate fluid in epidemiologic studies of breast disease. , 1993, Epidemiologic reviews.

[49]  A. Howell,et al.  Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast. , 1998, The American journal of clinical nutrition.

[50]  J. Madans,et al.  Use of postmenopausal hormone replacement therapy: estimates from a nationally representative cohort study. , 1997, American journal of epidemiology.

[51]  B. Henderson,et al.  Breast cancer and diet among the Japanese in Hawaii. , 1978, The American journal of clinical nutrition.

[52]  F. Sarkar,et al.  Soy isoflavone supplementation in healthy men prevents NF-κB activation by TNF-α in blood lymphocytes , 2001 .

[53]  G. Weber,et al.  Tamoxifen and genistein synergistically down-regulate signal transduction and proliferation in estrogen receptor-negative human breast carcinoma MDA-MB-435 cells. , 1999, Anticancer research.

[54]  W. Blair,et al.  Dietary soybean isolate and methionine supplementation affect mammary tumor progression in rats. , 1991, The Journal of nutrition.

[55]  H. Park,et al.  Quality of Dietary Protein During Initiation and Promotion of Chemical Carcinogenesis in Rats , 1992 .

[56]  P. Hughes,et al.  Do dietary phytoestrogens influence susceptibility to hormone-dependent cancer by disrupting the metabolism of endogenous oestrogens? , 2001, Biochemical Society transactions.

[57]  J. Ferlay,et al.  Estimates of the worldwide mortality from 25 cancers in 1990 , 1999, International journal of cancer.

[58]  G. Colditz,et al.  Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. , 1998, Journal of the National Cancer Institute.

[59]  K. Korach,et al.  Dietary Estrogens Act through Estrogen Receptor-Mediated Processes and Show No Antiestrogenicity in Cultured Breast Cancer Cells. , 1994, Environmental health perspectives.

[60]  M. Poutanen,et al.  Inhibition of 17β-Hydroxysteroid Oxidoreductase by Flavonoids in Breast and Prostate Cancer Cells , 1998 .

[61]  R. Ross,et al.  RESPONSE: re: effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin , 2000, Journal of the National Cancer Institute.

[62]  B. Henderson,et al.  Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. , 1991, British Journal of Cancer.

[63]  K. Gaido,et al.  Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[64]  H. Adlercreutz,et al.  Inhibition of human aromatase by mammalian lignans and isoflavonoid phytoestrogens , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[65]  C. Lowe,et al.  Age at first birth and breast cancer risk. , 1970, Bulletin of the World Health Organization.

[66]  J. Cameron,et al.  Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. , 1999, The Journal of clinical endocrinology and metabolism.

[67]  L. Skoog,et al.  Breast epithelial proliferation in postmenopausal women evaluated through fine-needle-aspiration cytology , 2001, Climacteric : the journal of the International Menopause Society.

[68]  A. Dart,et al.  Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[69]  Ashutosh Kumar Singh Development of QSAR Models to Predict Estrogenic, Carcinogenic, and Cancer Protective Effects of Phytoestrogens , 2001, Cancer investigation.

[70]  S. Barnes,et al.  Genistein inhibits both estrogen and growth factor-stimulated proliferation of human breast cancer cells. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[71]  Y. Ju,et al.  Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner. , 2001, Cancer research.

[72]  C. Laughton,et al.  Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study. , 1998, Environmental health perspectives.

[73]  K. Chew,et al.  Breast cancer incidence in women with abnormal cytology in nipple aspirates of breast fluid. , 1992, American journal of epidemiology.

[74]  M Carlquist,et al.  Structure of the ligand‐binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist , 1999, The EMBO journal.

[75]  R. Bostick,et al.  Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women. , 1996, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[76]  J. Erdman AHA Science Advisory: Soy protein and cardiovascular disease: A statement for healthcare professionals from the Nutrition Committee of the AHA. , 2000, Circulation.

[77]  M. Pike,et al.  Epidemiologic evidence for the increased cell proliferation model of carcinogenesis. , 1993, Environmental health perspectives.

[78]  M. Cobleigh,et al.  Hormone replacement therapy and high S phase in breast cancer. , 1999, JAMA.

[79]  S. Korourian,et al.  Diets containing whey proteins or soy protein isolate protect against 7,12-dimethylbenz(a)anthracene-induced mammary tumors in female rats. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[80]  K. Suh,et al.  Soybean ethanol extract increases the function of osteoblastic MC3T3-E1 cells. , 2001, Phytochemistry.

[81]  M. Yamaguchi,et al.  Anabolic effect of genistein in osteoblastic MC3T3-E1 cells. , 2000, International journal of molecular medicine.

[82]  A. Duncan,et al.  Modest hormonal effects of soy isoflavones in postmenopausal women. , 1999, The Journal of clinical endocrinology and metabolism.

[83]  K. Setchell,et al.  Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. , 2001, The Journal of nutrition.

[84]  A. Howell,et al.  Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast. , 1999, The Journal of clinical endocrinology and metabolism.

[85]  K. Griffiths,et al.  6Phytoestrogens and diseases of the prostate gland , 1998 .

[86]  R. A. King,et al.  Plasma and urinary kinetics of the isoflavones daidzein and genistein after a single soy meal in humans. , 1998, The American journal of clinical nutrition.

[87]  E. Scholar,et al.  Inhibition of invasion of murine mammary carcinoma cells by the tyrosine kinase inhibitor genistein. , 1994, Cancer letters.

[88]  D. Gridley,et al.  Modification of spontaneous mammary tumors in mice fed different sources of protein, fat and carbohydrate. , 1983, Cancer letters.

[89]  M. Pike,et al.  Soy intake and risk of breast cancer in Asians and Asian Americans. , 1998, The American journal of clinical nutrition.

[90]  C. Loprinzi,et al.  Estrogen deficiency: In search of symptom control and sexuality. , 2000, Journal of the National Cancer Institute.

[91]  Naxin Liu,et al.  Tyrosine kinase inhibitors as antiproliferative agents against an estrogen‐dependent breast cancer cell line in vitro , 1999, Journal of surgical oncology.

[92]  Linda Olson,et al.  Effects of Estrogen and EstrogenProgestin on Mammographic Parenchymal Density , 1999, Annals of Internal Medicine.

[93]  B. Henderson,et al.  Diet and breast cancer in Shanghai and Tianjin, China. , 1995, British Journal of Cancer.

[94]  T. Sellers,et al.  Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women's Health Study. , 1999, JAMA.

[95]  D. Stram,et al.  Meta-analysis: dietary fat intake, serum estrogen levels, and the risk of breast cancer. , 1999, Journal of the National Cancer Institute.

[96]  G. Jasienska,et al.  Lifestyle, hormones, and risk of breast cancer , 2001, BMJ : British Medical Journal.

[97]  M. Cordova,et al.  Hot flashes in postmenopausal women treated for breast carcinoma , 1998, Cancer.

[98]  B. V. VON Schoultz,et al.  Mammographic breast density during hormone replacement therapy: differences according to treatment. , 1999, American journal of obstetrics and gynecology.

[99]  G. Liu,et al.  Genistein-mediated attenuation of tamoxifen-induced antagonism from estrogen receptor-regulated genes. , 1998, Biochemical and biophysical research communications.

[100]  J. Gustafsson,et al.  Therapeutic potential of selective estrogen receptor modulators. , 1998, Current opinion in chemical biology.

[101]  S. Barnes,et al.  Mechanisms of action of the soy isoflavone genistein: emerging role for its effects via transforming growth factor beta signaling pathways. , 1998, The American journal of clinical nutrition.

[102]  P. Morris,et al.  The Phytoestrogen Genistein Reduces Bone Loss in Short-Term Ovariectomized Rats , 1998, Osteoporosis International.

[103]  M. Churchwell,et al.  Mass spectrometric determination of Genistein tissue distribution in diet-exposed Sprague-Dawley rats. , 2000, The Journal of nutrition.

[104]  R. Guzman,et al.  Hormonal prevention of breast cancer: mimicking the protective effect of pregnancy. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[105]  S. Bingham,et al.  Daidzein and genistein content of fruits and nuts. , 2000, The Journal of nutritional biochemistry.

[106]  L. Cohen Dietary fiber and breast cancer. , 1999, Anticancer research.

[107]  T. Sanders,et al.  The Phytoestrogen Genistein Produces Acute Nitric Oxide–Dependent Dilation of Human Forearm Vasculature With Similar Potency to 17&bgr;-Estradiol , 2001, Circulation.

[108]  K. Helzlsouer,et al.  Prevalence of menopausal symptoms among women with a history of breast cancer and attitudes toward estrogen replacement therapy. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[109]  J. Lampe,et al.  Urinary isoflavonoid phytoestrogen and lignan excretion after consumption of fermented and unfermented soy products. , 1995, Journal of the American Dietetic Association.

[110]  M. Martini,et al.  Effects of soy intake on sex hormone metabolism in premenopausal women. , 1999, Nutrition and cancer.

[111]  Linda K. Hirota,et al.  Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[112]  D. Grobbee,et al.  HRT and heart disease: Dr Jekyll or Mrs Hyde? , 2001, Maturitas.

[113]  S. Greenwood,et al.  The Role of Isoflavones in Menopausal Health: Consensus Opinion of The North American Menopause Society , 2000, Menopause.

[114]  E. Barrett-Connor,et al.  Timing of postmenopausal estrogen for optimal bone mineral density. The Rancho Bernardo Study. , 1997, JAMA.

[115]  R. Clarke,et al.  Maternal genistein exposure mimics the effects of estrogen on mammary gland development in female mouse offspring. , 1998, Oncology reports.

[116]  J. Eisman,et al.  Association between breast cancer and bone mineral density: the Dubbo Osteoporosis Epidemiology Study. , 2000, Maturitas.

[117]  M. Costanza,et al.  International variability in ages at menarche, first livebirth, and menopause. World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. , 1998, American journal of epidemiology.

[118]  Ross,et al.  RESPONSE: re: effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin , 2000, Journal of the National Cancer Institute.

[119]  Z. Shao,et al.  Genistein exerts multiple suppressive effects on human breast carcinoma cells. , 1998, Cancer research.

[120]  T. Badger,et al.  Urinary pharmacokinetics of the glucuronide and sulfate conjugates of genistein and daidzein. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[121]  C. Grubbs,et al.  Chemoprevention of N-Nitroso-N-methylurea-Induced Mammary Cancers by Pretreatment with 17β-Estradiol and Progesterone , 1985 .

[122]  H. Adlercreutz,et al.  Dietary phytoestrogens and cancer: in vitro and in vivo studies , 1992, The Journal of Steroid Biochemistry and Molecular Biology.

[123]  S. Barnes,et al.  Genistein inhibition of the growth of human breast cancer cells: independence from estrogen receptors and the multi-drug resistance gene. , 1991, Biochemical and biophysical research communications.

[124]  M. Pike,et al.  Increased cell division as a cause of human cancer. , 1990, Cancer research.

[125]  R. Miike,et al.  Breast cancer risk associated with abnormal cytology in nipple aspirates of breast fluid and prior history of breast biopsy. , 1993, American journal of epidemiology.

[126]  M. Messina Soy, soy phytoestrogens (isoflavones), and breast cancer. , 1999, The American journal of clinical nutrition.

[127]  A. Ekangaki,et al.  The effects of soy protein in women and men with elevated plasma lipids. , 2000, BioFactors.

[128]  H. Kim,et al.  Galectin-3 mediates genistein-induced G(2)/M arrest and inhibits apoptosis. , 2000, Carcinogenesis.

[129]  T. Aso,et al.  Soy Intake Related to Menopausal Symptoms, Serum Lipids, and Bone Mineral Density in Postmenopausal Japanese Women , 2001, Obstetrics and gynecology.

[130]  J. Gustafsson,et al.  Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. , 1998, Molecular pharmacology.

[131]  G. Hortobagyi,et al.  Obesity as an Adverse Prognostic Factor for Patients Receiving Adjuvant Chemotherapy for Breast Cancer , 1994, Annals of Internal Medicine.

[132]  T. Hunter Protein-Tryosine Kinases , 1985 .

[133]  Y. Kodera,et al.  Effects of Dietary, Drinking, and Smoking Habits on the Prognosis of Gastric Cancer , 2000, Nutrition and cancer.

[134]  H. Adlercreutz,et al.  Antiproliferative efficacy of lipophilic soy isoflavone phytoestrogens delivered by low density lipoprotein particles into cultured U937 cells. , 1999, Life sciences.

[135]  J. Russo,et al.  Susceptibility of the mammary gland to carcinogenesis: I Differentiation of the mammary gland as determinant of tumor incidence and type of lesion. , 1979, The American journal of pathology.

[136]  A. Franke,et al.  Serum levels and metabolic clearance of the isoflavones genistein and daidzein in hemodialysis patients. , 1999, Journal of the American Society of Nephrology : JASN.

[137]  S. Hulley,et al.  Hormones To Prevent Coronary Disease in Women: When Are Observational Studies Adequate Evidence? , 2000, Annals of Internal Medicine.

[138]  C. Riccardi,et al.  Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. , 1994, European journal of cancer.

[139]  K. Kitamura,et al.  Isoflavone Content in Brazilian Soybean Cultivars , 1995 .

[140]  W. Helferich,et al.  Genistein inhibits growth of estrogen-independent human breast cancer cells in culture but not in athymic mice. , 2000, The Journal of nutrition.

[141]  M. Pike,et al.  Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. , 1993, Epidemiologic reviews.

[142]  A. Purohit,et al.  Regulation of steroid sulphatase and oestradiol 17 beta-hydroxysteroid dehydrogenase in breast cancer. , 1999, Biochemical Society Transactions.

[143]  C. Dees,et al.  Dietary estrogens stimulate human breast cells to enter the cell cycle. , 1997, Environmental health perspectives.

[144]  S. Barnes,et al.  Soybeans inhibit mammary tumors in models of breast cancer. , 1990, Progress in clinical and biological research.

[145]  J. Santibañez,et al.  Genistein inhibits proliferation and in vitro invasive potential of human prostatic cancer cell lines. , 1997, Anticancer research.

[146]  N. Sathyamoorthy,et al.  Differential effects of dietary phyto-oestrogens daidzein and equol on human breast cancer MCF-7 cells. , 1997, European journal of cancer.

[147]  C. Rice-Evans,et al.  Antioxidant activity of phytoestrogenic isoflavones. , 1997, Free radical research.

[148]  Paul Cleary,et al.  Use of Hormone Replacement Therapy by Postmenopausal Women in the United States , 1999, Annals of Internal Medicine.

[149]  R. Mehta,et al.  Inhibition of N-methyl-N-nitrosourea-induced mammary tumors in rats by the soybean isoflavones. , 1996, Anticancer research.

[150]  J. Lampe,et al.  Wheat bran and soy protein feeding do not alter urinary excretion of the isoflavan equol in premenopausal women. , 2001, The Journal of nutrition.

[151]  Yiwei Li,et al.  Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435 cells by genistein. , 1999, International journal of oncology.

[152]  G. Howe High-fat diets and breast cancer risk. The epidemiologic evidence. , 1992, JAMA.

[153]  A. LaCroix,et al.  Bone mineral density and breast cancer risk in postmenopausal women. , 2001, Journal of clinical epidemiology.

[154]  S. Barnes,et al.  Potential role of dietary isoflavones in the prevention of cancer. , 1994, Advances in experimental medicine and biology.

[155]  G. S. Pope,et al.  The interaction in the immature mouse of potent oestrogens with coumestrol, genistein and other utero-vaginotrophic compounds of low potency. , 1966, The Journal of endocrinology.

[156]  D. Rubinow,et al.  Estrogen-progestin replacement and risk of breast cancer. , 2000, JAMA.

[157]  K. Dohi,et al.  Chemoprevention of N‐Nitroso‐N‐methylurea‐induced Rat Mammary Carcinogenesis by Soy Foods or Biochanin A , 1998, Japanese journal of cancer research : Gann.

[158]  N. Day,et al.  Dietary effects on breast-cancer risk in Singapore , 1991, The Lancet.

[159]  K. Grandien,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors � and � , 2022 .

[160]  S. O’Brien,et al.  Clonal variation of MCF-7 breast cancer cells in vitro and in athymic nude mice. , 1983, Cancer research.

[161]  M. Pike,et al.  Effects of soy foods on ovarian function in premenopausal women , 2000, British Journal of Cancer.

[162]  Hormone Replacement Therapy After a Diagnosis of Breast Cancer in Relation to Recurrence and Mortality , 2001 .

[163]  R. Clarke,et al.  Prepubertal exposure to zearalenone or genistein reduces mammary tumorigenesis , 1999, British Journal of Cancer.

[164]  G. Berglund,et al.  Increased incidence of small and well‐differentiated breast tumours in post‐menopausal women following hormone‐replacement therapy , 2001, International journal of cancer.

[165]  C. Falany,et al.  The role of metabolism in mammary epithelial cell growth inhibition by the isoflavones genistein and biochanin A. , 1996, Carcinogenesis.

[166]  M. Wrensch,et al.  Alternative therapies used by women with breast cancer in four ethnic populations. , 2000, Journal of the National Cancer Institute.

[167]  H. Adlercreutz,et al.  Genistein, a dietary-derived inhibitor of in vitro angiogenesis. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[168]  P. Murphy,et al.  Daidzein is a more bioavailable soymilk isoflavone than is genistein in adult women. , 1994, The Journal of nutrition.

[169]  E. Briganti,et al.  Phytoestrogens and breast cancer in postmenopausal women: a case control study , 2000, Menopause.

[170]  M. Ball,et al.  Effects of replacing meat with soyabean in the diet on sex hormone concentrations in healthy adult males , 2000, British Journal of Nutrition.

[171]  T. Toda,et al.  Preventive effects of the plant isoflavones, daidzin and genistin, on bone loss in ovariectomized rats fed a calcium-deficient diet. , 1998, Biological & pharmaceutical bulletin.

[172]  D. Zava,et al.  Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. , 1997, Nutrition and cancer.

[173]  C. Lamartiniere Protection against breast cancer with genistein: a component of soy. , 2000, The American journal of clinical nutrition.

[174]  E B Larson,et al.  Effect of postmenopausal hormonal replacement therapy on mammographic density and parenchymal pattern. , 1995, Radiology.

[175]  B. V. VON Schoultz,et al.  Mammographic breast density during hormone replacement therapy: effects of continuous combination, unopposed transdermal and low-potency estrogen regimens , 2001, Climacteric : the journal of the International Menopause Society.

[176]  R. Clarke,et al.  Maternal exposure to genistein during pregnancy increases carcinogen-induced mammary tumorigenesis in female rat offspring. , 1999, Oncology reports.

[177]  V. Ernster,et al.  Birthplace and yield of nipple aspirate fluid in Chinese women. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[178]  H. Adlercreutz,et al.  Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. , 1997, Cancer research.

[179]  H. Adlercreutz,et al.  Dietary soybean may be antiestrogenic in male mice. , 1995, The Journal of nutrition.

[180]  M. Blankenstein,et al.  Concentration of Sex Steroids in Adipose Tissue after Menopause , 1998, Steroids.

[181]  A. Duncan,et al.  Premenopausal equol excretors show plasma hormone profiles associated with lowered risk of breast cancer. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[182]  D. Campbell,et al.  Flavonoid inhibition of aromatase enzyme activity in human preadipocytes , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[183]  A. Brzezinski,et al.  Phytoestrogens: the "natural" selective estrogen receptor modulators? , 1999, European journal of obstetrics, gynecology, and reproductive biology.

[184]  J. Russo,et al.  DNA labeling index and structure of the rat mammary gland as determinants of its susceptibility to carcinogenesis. , 1978, Journal of the National Cancer Institute.

[185]  C. Lamartiniere,et al.  Genistein, a component of soy, inhibits the expression of the EGF and ErbB2/Neu receptors in the rat dorsolateral prostate , 1998, The Prostate.

[186]  S. Cummings,et al.  Effects of hormone replacement therapy on clinical fractures and height loss: The Heart and Estrogen/Progestin Replacement Study (HERS). , 2001, The American journal of medicine.

[187]  P. Murphy,et al.  Isoflavone composition of American and Japanese soybeans in Iowa: effects of variety, crop year, and location , 1994 .

[188]  G. Blackburn,et al.  Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. , 1999, The Journal of nutrition.

[189]  S. Cummings,et al.  Bone Mineral Density and Risk of Breast Cancer Differences by Family History of Breast Cancer , 1998 .

[190]  J. K. Day,et al.  Dietary Genistein Increased DMBA-Induced Mammary Adenocarcinoma in Wild-Type, but Not ERαKO, Mice , 2001, Nutrition and cancer.

[191]  G. Gordon,et al.  Soy, its components, and cancer prevention: a review of the in vitro, animal, and human data. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[192]  A. Linos,et al.  Urinary estrogen metabolites and mammographic parenchymal patterns in postmenopausal women. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[193]  P. Murphy,et al.  Bioavailability of soybean isoflavones depends upon gut microflora in women. , 1995, The Journal of nutrition.

[194]  D. Epner,et al.  Molecular Mechanisms of Cell Cycle Block by Methionine Restriction in Human Prostate Cancer Cells , 2000, Nutrition and cancer.

[195]  M. Mcguire,et al.  Soybean isoflavones reduce experimental metastasis in mice. , 1999, The Journal of nutrition.

[196]  A. Williams,et al.  Nutrition During and After Cancer Treatment: A Guide * for Informed Choices by Cancer Survivors , 2001, CA: a cancer journal for clinicians.

[197]  K K Carroll,et al.  Experimental evidence of dietary factors and hormone-dependent cancers. , 1975, Cancer research.

[198]  S. Haslam,et al.  Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. , 1998, Cancer research.

[199]  J. Gustafsson,et al.  Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors α and β , 1999 .

[200]  R. Lobo,et al.  Vasomotor Symptom Relief by Soy Isoflavone Extract Tablets in Postmenopausal Women: A Multicenter, Double‐Blind, Randomized, Placebo‐Controlled Study , 2000, Menopause.

[201]  A. Duncan,et al.  Soy isoflavones exert modest hormonal effects in premenopausal women. , 1999, The Journal of clinical endocrinology and metabolism.

[202]  S. Barsky,et al.  Genistein's "ER-dependent and independent" actions are mediated through ER pathways in ER-positive breast carcinoma cell lines. , 2000, Anticancer research.

[203]  M. Pike,et al.  Ethnic differences in post-menopausal plasma oestrogen levels: high oestrone levels in Japanese-American women despiteow weight , 2000, British Journal of Cancer.

[204]  L. Fioravanti,et al.  Genistein in the control of breast cancer cell growth: insights into the mechanism of action in vitro. , 1998, Cancer letters.

[205]  H. Adlercreutz,et al.  Plasma concentrations of phyto-oestrogens in Japanese men , 1993, The Lancet.

[206]  E. Ealley,et al.  Maternal and prepubertal diet, mammary development and breast cancer risk. , 2001, The Journal of nutrition.

[207]  T. Sugimura,et al.  Inhibitory effects of Bifidobacterium-fermented soy milk on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced rat mammary carcinogenesis, with a partial contribution of its component isoflavones. , 2000, Carcinogenesis.

[208]  M. Inoue,et al.  A Large‐scale, Hospital‐based Case‐Control Study of Risk Factors of Breast Cancer According to Menopausal Status , 1995, Japanese journal of cancer research : Gann.

[209]  A. Duncan,et al.  Soy consumption alters endogenous estrogen metabolism in postmenopausal women. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[210]  S. Haslam,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 1999 by The Endocrine Society Hormone Replacement Therapy with Estrogen or Estrogen plus Medroxyprogesterone Acetate Is Associated with Increased Epithelial Proliferation , 2022 .

[211]  W. Welshons,et al.  The Effective Free Fraction of Estradiol and Xenoestrogens in Human Serum Measured by Whole Cell Uptake Assays: Physiology of Delivery Modifies Estrogenic Activity , 1998, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[212]  J. Crouse,et al.  A randomized trial comparing the effect of casein with that of soy protein containing varying amounts of isoflavones on plasma concentrations of lipids and lipoproteins. , 1999, Archives of internal medicine.

[213]  F. Speizer,et al.  Intake of fruits and vegetables and risk of breast cancer: a pooled analysis of cohort studies. , 2001, JAMA.

[214]  H. Iishi,et al.  Genistein attenuates peritoneal metastasis of azoxymethane‐induced intestinal adenocarcinomas in Wistar rats , 2000 .

[215]  A. Palotie,et al.  Regulation of sex hormone-binding globulin production by isoflavonoids and patterns of isoflavonoid conjugation in HepG2 cell cultures , 1995, Steroids.

[216]  D. Leitman,et al.  Estrogen Receptor β-Selective Transcriptional Activity and Recruitment of Coregulators by Phytoestrogens* , 2001, The Journal of Biological Chemistry.

[217]  K. Nahoul,et al.  Endometrium and plasma hormone profile in the peri-menopause and post-menopause. , 1986, Maturitas.

[218]  K. Setchell,et al.  Biological effects of isoflavones in young women: importance of the chemical composition of soyabean products , 1995, British Journal of Nutrition.

[219]  D. Kiel,et al.  Bone mass and the risk of breast cancer among postmenopausal women. , 1997, The New England journal of medicine.

[220]  R. Tuimala,et al.  Why do postmenopausal women discontinue hormone replacement therapy? , 1999, Maturitas.

[221]  N F Boyd,et al.  Mammographic density as a marker of susceptibility to breast cancer: a hypothesis. , 2001, IARC scientific publications.

[222]  B. Modan,et al.  Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies. , 1990, Journal of the National Cancer Institute.

[223]  C. Nagata,et al.  Decreased serum total cholesterol concentration is associated with high intake of soy products in Japanese men and women. , 1998, The Journal of nutrition.

[224]  W. Grizzle,et al.  The effect of isolated soy protein on plasma biomarkers in elderly men with elevated serum prostate specific antigen. , 1999, The Journal of urology.

[225]  K. Setchell,et al.  Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. , 1994, The American journal of clinical nutrition.

[226]  M. Shibuya,et al.  Genistein, a specific inhibitor of tyrosine-specific protein kinases. , 1987, The Journal of biological chemistry.

[227]  J. Potter,et al.  Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[228]  S. Barnes,et al.  Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats. , 1996, Carcinogenesis.

[229]  H. Adlercreutz,et al.  Interindividual Variation in Metabolism of Soy Isoflavones and Lignans: Influence of Habitual Diet on Equol Production by the Gut Microflora , 2000, Nutrition and cancer.

[230]  S. C. Garner,et al.  1Phytoestrogens and bone , 1998 .

[231]  S. Barnes,et al.  Genistein suppresses mammary cancer in rats. , 1995, Carcinogenesis.

[232]  A. Morrison,et al.  Some international differences in treatment and survival in breast cancer , 1976, International journal of cancer.

[233]  C. Dollbaum,et al.  Estrogen and Progestin Bioactivity of Foods, Herbs, and Spices , 1998, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[234]  S. Cummings,et al.  Bone mass and breast cancer risk in older women: differences by stage at diagnosis. , 2001, Journal of the National Cancer Institute.

[235]  S. Barnes,et al.  Neonatal Genistein Chemoprevents Mammary Cancer , 1995, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[236]  K. Dohi,et al.  Chemoprevention of N‐Nitroso‐N‐methylurea‐induced Rat Mammary Cancer by Miso and Tamoxifen, Alone and in Combination , 1998, Japanese journal of cancer research : Gann.

[237]  M. A. Palma,et al.  Dietary isoflavones affect sex hormone-binding globulin levels in postmenopausal women. , 2000, The Journal of clinical endocrinology and metabolism.

[238]  L. Skoog,et al.  Proliferation of breast epithelial cells in healthy women during the menstrual cycle. , 1997, American journal of obstetrics and gynecology.

[239]  D. M. Lubián López,et al.  Prognosis of breast cancers detected in women receiving hormone replacement therapy. , 2001, Maturitas.

[240]  G. Hortobagyi,et al.  Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[241]  C K Osborne,et al.  Selective estrogen receptor modulators: structure, function, and clinical use. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[242]  A M Nomura,et al.  Tofu and risk of breast cancer in Asian-Americans. , 1996, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[243]  A. Tamakoshi,et al.  Dietary intake and sources of isoflavones among Japanese. , 1999, Nutrition and cancer.

[244]  S. Cummings,et al.  Postmenopausal hormone therapy for prevention of fractures: how good is the evidence? , 2001, JAMA.

[245]  L Fioravanti,et al.  The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function , 1999, British Journal of Cancer.

[246]  H. Tokuda,et al.  Antitumor effects of soybean hypocotyls and soybeans on the mammary tumor induction by N-methyl-n-nitrosourea in F344 rats. , 2000, Anticancer research.

[247]  D. N. Kirk,et al.  Nonsteroidal estrogens of dietary origin: possible roles in hormone-dependent disease. , 1984, The American journal of clinical nutrition.

[248]  G. Beecher,et al.  Isoflavones in retail and institutional soy foods. , 1999, Journal of agricultural and food chemistry.

[249]  E. Huberman,et al.  Induction of differentiation and DNA strand breakage in human HL-60 and K-562 leukemia cells by genistein. , 1990, Cancer research.

[250]  J. Corton,et al.  Interaction of Estrogenic Chemicals and Phytoestrogens with Estrogen Receptor β. , 1998, Endocrinology.

[251]  Julian Peto,et al.  Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer , 1997, The Lancet.

[252]  G. Habrioux,et al.  Effects of phytoestrogens on aromatase, 3β and 17β-hydroxysteroid dehydrogenase activities and human breast cancer cells. , 2000 .

[253]  L. Hilakivi-Clarke,et al.  Genistein: does it prevent or promote breast cancer? , 2000, Environmental health perspectives.

[254]  G. Graef,et al.  Effect of dietary supplementation of soybeans on experimental metastasis of melanoma cells in mice. , 1997, Nutrition and cancer.

[255]  K. Setchell,et al.  Animal Models Impacted by Phytoestrogens in Commercial Chow: Implications for Pathways Influenced by Hormones , 2001, Laboratory Investigation.

[256]  C. Nagata,et al.  Ecological study of the association between soy product intake and mortality from cancer and heart disease in Japan. , 2000, International journal of epidemiology.

[257]  L. Wilkens,et al.  Ethnic differences and factors related to breast cancer survival in Hawaii. , 1997, International journal of epidemiology.

[258]  S. Barnes,et al.  Soy intake and cancer risk: a review of the in vitro and in vivo data. , 1994, Nutrition and cancer.

[259]  A. Duncan,et al.  Effects of soy isoflavones on estrogen and phytoestrogen metabolism in premenopausal women. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[260]  S. Potter,et al.  Soy protein and cardiovascular disease: the impact of bioactive components in soy. , 2009, Nutrition reviews.

[261]  K. Anderson,et al.  Effects of soya consumption for one month on steroid hormones in premenopausal women: implications for breast cancer risk reduction. , 1996, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[262]  S. Newman,et al.  The effect of body mass index and oestrogen receptor level on survival of breast cancer patients. , 1997, International journal of epidemiology.

[263]  M. Nair,et al.  Effect of isoflavones genistein and daidzein in the inhibition of lung metastasis in mice induced by B16F-10 melanoma cells. , 1998, Nutrition and cancer.

[264]  M. Kurzer,et al.  Effects of phytoestrogens on DNA synthesis in MCF-7 cells in the presence of estradiol or growth factors. , 1998, Nutrition and cancer.

[265]  G. Falciglia,et al.  Evolution of meal patterns and food choices of Japanese-American females born in the United States , 2000, European Journal of Clinical Nutrition.

[266]  J. Ishida,et al.  A specific inhibitor for tyrosine protein kinase from Pseudomonas. , 1986, The Journal of antibiotics.