Estrogen Receptor β-Selective Transcriptional Activity and Recruitment of Coregulators by Phytoestrogens

Estrogens used in hormone replacement therapy regimens may increase the risk of developing breast cancer. Paradoxically, high consumption of plant-derived phytoestrogens, particularly soybean isoflavones, is associated with a low incidence of breast cancer. To explore the molecular basis for these potential different clinical outcomes, we investigated whether soybean isoflavones elicit distinct transcriptional actions from estrogens. Our results demonstrate that the estrogen 17β-estradiol effectively triggers the transcriptional activation and repression pathways with both estrogen receptors (ERs) ERα and ERβ. In contrast, soybean isoflavones (genistein, daidzein, and biochanin A) are ERβ-selective agonists of transcriptional repression and activation at physiological levels. The molecular mechanism for ERβ selectivity by isoflavones involves their capacity to create an activation function-2 surface of ERβ that has a greater affinity for coregulators than ERα. Phytoestrogens may act as natural selective estrogen receptor modulators that elicit distinct clinical effects from estrogens used for hormone replacement by selectively recruiting coregulatory proteins to ERβ that trigger transcriptional pathways. Estrogens used in hormone replacement therapy regimens may increase the risk of developing breast cancer. Paradoxically, high consumption of plant-derived phytoestrogens, particularly soybean isoflavones, is associated with a low incidence of breast cancer. To explore the molecular basis for these potential different clinical outcomes, we investigated whether soybean isoflavones elicit distinct transcriptional actions from estrogens. Our results demonstrate that the estrogen 17β-estradiol effectively triggers the transcriptional activation and repression pathways with both estrogen receptors (ERs) ERα and ERβ. In contrast, soybean isoflavones (genistein, daidzein, and biochanin A) are ERβ-selective agonists of transcriptional repression and activation at physiological levels. The molecular mechanism for ERβ selectivity by isoflavones involves their capacity to create an activation function-2 surface of ERβ that has a greater affinity for coregulators than ERα. Phytoestrogens may act as natural selective estrogen receptor modulators that elicit distinct clinical effects from estrogens used for hormone replacement by selectively recruiting coregulatory proteins to ERβ that trigger transcriptional pathways. hormone replacement therapy selective estrogen receptor modulator 17β-estradiol estrogen receptor activation function-2 glutathione S-transferase tumor necrosis factor thymidine kinase reverse transcription polymerase chain reaction TNF responsive element estrogen response element Estrogens are used in hormone replacement therapy (HRT)1 to prevent hot flashes, urogenital atrophy, and osteoporosis in postmenopausal women (1Johnson S.R. Med. Clin. N. Am. 1998; 82: 297-320Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 2Kenny A.M. Prestwood K.M. Rheum. Dis. Clin. N. Am. 2000; 26: 569-591Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). HRT also may prevent heart disease (3Bush T.L. J. Reprod. Med. 2000; 45: 259-273PubMed Google Scholar), Alzheimer's disease (4van Duijn C.M. Maturitas. 1999; 31: 201-205Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar), and colon cancer (5Grodstein F. Newcomb P.A. Stampfer M.J. Am. J. Med. 1999; 106: 574-582Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar). Unfortunately, HRT has not lived up to its potential to improve the health of women, because estrogens have been associated with an increased incidence of breast (6Collaborative Group on Hormonal Factors in Breast Cancer, Lancet, 350, 1997, 1047, 1059Google Scholar, 7Colditz G.A. J. Womens Health. 1999; 8: 347-357Crossref PubMed Scopus (33) Google Scholar) and endometrial cancer (8Pickar J.H. Thorneycroft I. Whitehead M. Am. J. Obstet. Gynecol. 1998; 178: 1087-1099Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). This relationship has hampered compliance with HRT severely and has sparked an intense pursuit for selective estrogen receptor modulators (SERMs) that have a safer profile (9Baker V.L. Leitman D. Jaffe R.B. Obstet. Gynecol. Surv. 2000; 55: S21-S47Crossref PubMed Scopus (36) Google Scholar, 10McDonnell D.P. J. Soc. Gynecol. Investig. 2000; 7: S10-S15Crossref PubMed Google Scholar). Recently, raloxifene has been approved for the prevention and treatment of osteoporosis (11Clemett D. Spencer C.M. Drugs. 2000; 60: 379-411Crossref PubMed Scopus (122) Google Scholar). Raloxifene is classified as a SERM because it exhibits agonist activity in some tissues such as the bone (12Delmas P. Bjarnason N. Mitlak B. Ravoux A.-C. Shah A. Huster W. Draper M. Christiansen C. N. Engl. J. Med. 1997; 337: 1641-1647Crossref PubMed Scopus (1606) Google Scholar, 13Ettinger B. Black D. Mitlak B. Knickerbocker R. Nickelsen T. Genant H. Christiansen C. Delmas P. J. Am. Med. Assoc. 1999; 282: 637-644Crossref PubMed Scopus (3138) Google Scholar) and acts as an antagonist in other tissues including the breast (14Cummings S.R. Eckert S. Krueger K.A. Grady D. Powles T.J. Cauley J.A. Norton L. Nickelsen T. Bjarnason N.H. Morrow M. Lippman M.E. Black D. Glusman J.E. Costa A. Jordan V.C. J. Am. Med. Assoc. 1999; 281: 2189-2197Crossref PubMed Scopus (1862) Google Scholar). Although these effects are extremely desirable, raloxifene also increases hot flashes (15Davies G. Huster W. Lu Y. Plouffe Jr., L. Lakshmanan M. Obstet. Gynecol. 1999; 93: 558-565Crossref PubMed Scopus (180) Google Scholar), is weaker than estrogens at increasing bone mineral density (16Sato M. Rippy M.K. Bryant H.U. FASEB J. 1996; 10: 905-912Crossref PubMed Scopus (264) Google Scholar), and does not improve cognitive function (17Nickelson T. Lufkin E. Riggs B. Cox D. Crook T. Psychoneuroendocrinology. 1999; 24: 115-128Crossref PubMed Scopus (127) Google Scholar) or prevent hip fracture (13Ettinger B. Black D. Mitlak B. Knickerbocker R. Nickelsen T. Genant H. Christiansen C. Delmas P. J. Am. Med. Assoc. 1999; 282: 637-644Crossref PubMed Scopus (3138) Google Scholar). Thus, the quest for superior SERMs for HRT continues to be intense. There also is a growing interest in using dietary natural plant estrogens (phytoestrogens), particularly those found in soy products, as a potential alternative to the estrogens in HRT (18Clarkson T. Anthony M. Williams J. Honoré E. Cline J. Proc. Soc. Exp. Biol. Med. 1998; 217: 365-368Crossref PubMed Scopus (109) Google Scholar). Interest in phytoestrogens has been fueled by observational studies showing a lower incidence of menopausal symptoms, osteoporosis, cardiovascular disease, and breast and endometrial cancers in Asian women who have a diet rich in soy products (19Ingram D. Sanders K. Kolybaba M. Lopez D. Lancet. 1997; 350: 990-994Abstract Full Text Full Text PDF PubMed Scopus (681) Google Scholar, 20Goodman M.T. Wilkens L.R. Hankin J.H. Lyu L.C. Wu A.H. Kolonel L.N. Am. J. Epidemiol. 1997; 146: 294-306Crossref PubMed Scopus (315) Google Scholar, 21Adlercreutz H. Baillieres Clin. Endocrinol. Metab. 1998; 12: 605-623Abstract Full Text PDF PubMed Scopus (223) Google Scholar, 22Murkies A. Wilcox G. Davis S. J. Clin. Endocrinol. Metab. 1998; 83: 297-303Crossref PubMed Scopus (465) Google Scholar, 23Tham D. Gardner C. Haskell W. J. Clin. Endocrinol. Metab. 1998; 83: 2223-2235Crossref PubMed Scopus (746) Google Scholar, 24Davis S.R. Dalais F.S. Simpson E.R. Murkies A.L. Recent Prog. Horm. Res. 1999; 54: 185-210PubMed Google Scholar). Consistent with epidemiological studies are the findings that soy phytoestrogens prevent mammary tumors (25Barnes S. Baillieres Clin. Endocrinol. Metab. 1998; 12: 559-570Abstract Full Text PDF PubMed Scopus (104) Google Scholar, 26Lamartiniere C.A. Murrill W.B. Manzolillo P.A. Zhang J.X. Barnes S. Zhang X. Wei H. Brown N.M. Proc. Soc. Exp. Biol. Med. 1998; 217: 358-364Crossref PubMed Scopus (152) Google Scholar) and bone loss (27Arjmandi B. Alekel L. Hollis B. Amin D. Stacewica-Sapuntzaki M. Guo P. Kukreja S. J. Nutr. 1996; 126: 161-167Crossref PubMed Scopus (478) Google Scholar, 28Picherit C. Coxam V. Bennetau-Pelissero C. Kati-Coulibaly S. Davicco M.J. Lebecque P. Barlet J.P. J. Nutr. 2000; 130: 1675-1681Crossref PubMed Scopus (266) Google Scholar) in rodents and atherosclerosis of coronary arteries in monkeys (29Anthony M. Clarkson T. Bullock B. Wagner J. Arterioscler. Throm. Vasc. Biol. 1997; 17: 2524-2531Crossref PubMed Scopus (246) Google Scholar). Soy protein relieves hot flashes in postmenopausal women (30Albertazzi P. Pansini F. Bonaccorsi G. Zanotti L. Forini E. De Aloysio D. Obstet. Gynecol. 1998; 91: 6-11Crossref PubMed Scopus (441) Google Scholar) and attenuates bone loss in the lumbar spine of perimenopausal women (31Alekel D.L. Germain A.S. Peterson C.T. Hanson K.B. Stewart J.W. Toda T. Am. J. Clin. Nutr. 2000; 72: 844-852Crossref PubMed Scopus (479) Google Scholar). Furthermore, a high intake of dietary phytoestrogens is associated with a lower incidence of breast cancer in women (19Ingram D. Sanders K. Kolybaba M. Lopez D. Lancet. 1997; 350: 990-994Abstract Full Text Full Text PDF PubMed Scopus (681) Google Scholar). Many postmenopausal women are taking phytoestrogens in an effort to alleviate menopausal symptoms without increasing their risk of developing breast cancer. Moreover, many women with a history of breast cancer take phytoestrogens to control menopausal symptoms (32Lee M.M. Lin S.S. Wrensch M.R. Adler S.R. Eisenberg D. J. Natl. Cancer Inst. 2000; 92: 42-47Crossref PubMed Scopus (319) Google Scholar, 33Morris K.T. Johnson N. Homer L. Walts D. Am. J. Surg. 2000; 179: 407-411Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar) because estrogens are contraindicated. The isoflavones, genistein, daidzein, and biochanin A, which are abundant in soybeans (34Setchell K.D. Am. J. Clin. Nutr. 1998; 68 Suppl. 6: 1333-1346Crossref Scopus (1012) Google Scholar) and available widely as herbal tablets, are especially popular among postmenopausal women. Despite their popularity and putative health benefits it is clear that we need to know much more about the molecular mechanisms, safety, and efficacy of isoflavones before they can be recommended to postmenopausal women as an alternative to estrogens for HRT. However, it is clearly important to elucidate the molecular mechanisms whereby isoflavones may elicit distinct clinical actions from estrogens used in HRT. Isoflavones have a structure similar to that of 17β-estradiol (E2) and are capable of binding to the two known estrogen receptors, ERα and ERβ (35Green S. Walter P. Greene G. Krust A. Goffin C. Jensen E. Scrace G. Waterfield M. Chambon P. J. Steroid Biochem. 1986; 24: 77-83Crossref PubMed Scopus (238) Google Scholar, 36Kuiper G.G. Enmark E. Pelto-Huikko M. Nilsson S. Gustafsson J.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 5925-5930Crossref PubMed Scopus (4239) Google Scholar, 37Mosselman S. Polman J. Dijkema R. FEBS Lett. 1996; 392: 49-53Crossref PubMed Scopus (2060) Google Scholar). Compared with ERα, ERβ exhibits a 7–30-fold greater binding affinity for genistein, whereas E2 binds to ERα and ERβ with equal affinity (38Kuiper G. Carlsson B. Grandien K. Enmark E. Haggblad J. Nilsson S. Gustafsson J. Endocrinology. 1997; 138: 863-870Crossref PubMed Scopus (3678) Google Scholar, 39Barkhem T. Carlsson B. Nilsson Y. Enmark E. Gustafsson J. Nilsson S. Mol. Pharmacol. 1998; 54: 105-112Crossref PubMed Scopus (723) Google Scholar). The relatively selective binding of genistein to ERβ indicates that isoflavones may produce distinct clinical effects from estrogens by selectively triggering ERβ-mediated transcriptional pathways or differentially triggering transcriptional activation or repression pathways by ERβ. To test this hypothesis, we compared the effects of isoflavones and E2 on transcriptional repression and activation in the presence of ERα or ERβ. Our data demonstrate that isoflavones selectively trigger the transcriptional pathways of ERβ, particularly transcriptional repression. In addition to selectively binding to ERβ, our results suggest that the ERβ selectivity of isoflavones involves their capacity to induce an activation function-2 (AF-2) surface of ERβ that has greater affinity for coregulators such as glucocorticoid interacting receptor protein 1 (GRIP1) (40Hong H. Kohli K. Trivedi A. Johnson D.L. Stallcup M.R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar) compared with ERα. Phytoestrogens may act as natural SERMs by selectively recruiting coregulators that trigger ERβ-mediated transcriptional pathways. ERα and ERβ by P. Chambon and J. P. Gustafsson J.A. Leitman Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus (180) Google Scholar). and by M. Stallcup P. P. J. C. W. D. S. E. Stallcup M.R. Mol. Endocrinol. 1998; 12: PubMed Scopus Google Scholar). of the to E.R. J. Biol. Full Text PDF PubMed Google Scholar) or of the from the the of to thymidine kinase to and the element in the and of the at the to of the and of the to and from the at the of as E.R. Williams T. Mol. Biol. 12: PubMed Google Scholar), whereas and and in and to a and with a as J. P. Gustafsson J.A. Leitman Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus (180) Google Scholar) using of and 1 of ERα or ERβ the in and at 1 in The with genistein, daidzein, or biochanin to to for at with of and activity using a available The of hormone to produce a or of activity with the at 1 in the presence of and the growing for ERα as by reverse transcription polymerase chain reaction The in at a density of in they with increasing of E2 or The other and E2 or genistein to the the with a in the at and the data similar in with for with 1 genistein and to for 1 at and using to the using and reverse as recommended by the using for the and or and using the or The products on a with The breast cancer R. R. M. J. Natl. Cancer Inst. PubMed Scopus Google Scholar), by with ERα. The in the at 1 in the presence of The of ERα and which by in the as P. P. C. Lopez E. Enmark E. Gustafsson J.A. Nilsson S. Mol. Endocrinol. 1999; PubMed Google Scholar). ERα and ERβ and in the and binding a of to in the presence of control or The at for of the the proteins with and on a The by and using the and To the effects of isoflavones on transcriptional we used the to E.R. J. Biol. Full Text PDF PubMed Google Scholar) of the because this activation and E2 repression J. P. Gustafsson J.A. Leitman Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus (180) Google Scholar). E2 a repression of activation of the of a with ERα A) or ERβ in and biochanin on activation of the with ERα, whereas genistein a repression at 1 1 In contrast, isoflavones a repression of activation of in the presence of ERβ is the and is about weaker than E2 at repression The isoflavones are more also at triggering transcriptional activation of a estrogen response element in with ERβ compared with ERα However, isoflavones are about more at triggering transcriptional repression compared with transcriptional activation with ERβ (genistein, daidzein, biochanin A, selectively transcription of an of the of the with 1 of for ERα or ERβ the for with increasing of genistein, daidzein, or biochanin A, and activity data the of The of genistein on investigated in a because these ERα and ERβ, as by not and is in the of osteoporosis R. J. Res. 1996; PubMed Scopus Google Scholar). with E2 or genistein for and to for 1 a of as by that by E2 or genistein The that genistein in that repression of transcription by genistein is physiological and not by of transcriptional by To which is for the we with ERα or ERβ. Although the are capable of the they are not in high to the of the that genistein is at the in with ERβ not ERα. results that genistein the ERβ also ERα. Our results that isoflavones selectively ERβ-mediated To explore the activity of genistein on ERα in breast cancer we compared the effects of E2 and genistein on ERα activation of in an breast cancer with ERα and on the of which ERα not ERβ as by not to and genistein is much weaker than E2 at an in the ERα A) and the of Thus, genistein is a ERα agonist in and or with ERα and in that ERα potential for ERβ-selective activity is that isoflavones induce a surface in ERβ not ERα because we that the surface is for repression J. P. Gustafsson J.A. Leitman Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus (180) Google Scholar). Consistent with this is the that an ERβ with a in of the surface to repression in response to genistein binding of coregulatory proteins R.B. 1999; PubMed Scopus Google Scholar, 2000; PubMed Google Scholar) to the surface is for repression by E2 J. P. Gustafsson J.A. Leitman Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus (180) Google Scholar), we compared the effects of E2 and genistein on that at the the (40Hong H. Kohli K. Trivedi A. Johnson D.L. Stallcup M.R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar), and ERα or ERβ. these a response element in the of an in the which is for activation and E2 repression J. P. Gustafsson J.A. Leitman Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus (180) Google Scholar). used for these studies of because not to the J. P. Gustafsson J.A. Leitman Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus (180) Google Scholar) may be to the coregulators such as not E2 is extremely at activation of in the presence of ERα A) or ERβ for ERα, and for In contrast, genistein is much more at activation with ERβ compared with ERα Furthermore, at genistein a repression with ERα compared with a repression with ERβ at selectively activation of that the element in the and of the at the to of the the is this is in the of with and ERα or ERβ and with increasing of E2 or genistein for and activity by about in the of E2 or data the of results suggest that genistein an surface in ERβ that the binding of more compared with ERα. To this with ERα or ERβ in the presence of E2 or similar increase in binding of ERα or ERβ to with E2 In contrast, genistein is more at the and ERβ binding of ERβ to is greater than with ERα. findings demonstrate that genistein an surface in ERβ that has a affinity for than that in ERα. Estrogens in HRT improve menopausal symptoms are associated with an increased risk of breast (6Collaborative Group on Hormonal Factors in Breast Cancer, Lancet, 350, 1997, 1047, 1059Google Scholar, 7Colditz G.A. J. Womens Health. 1999; 8: 347-357Crossref PubMed Scopus (33) Google Scholar) and endometrial cancer (8Pickar J.H. Thorneycroft I. Whitehead M. Am. J. Obstet. Gynecol. 1998; 178: 1087-1099Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). To the effects of women with a are also with in HRT Unfortunately, the addition of may increase the risk of breast cancer A.M. C.A. J. Clin. Endocrinol. Metab. 1999; PubMed Scopus Google Scholar, C. J. R. S. L. R. J. Am. Med. Assoc. 2000; PubMed Scopus Google Scholar) and potential benefits of estrogens on the cardiovascular L. Maturitas. 1998; 31: Full Text Full Text PDF PubMed Scopus Google Scholar). The is to estrogens that their to prevent menopausal symptoms without breast cancer or for The of more estrogens for HRT a greater of different differentially activation and repression by ERα and ERβ. have that isoflavones elicit distinct transcriptional actions from estrogens. E2 effectively triggers both and ERβ-mediated transcriptional activation or repression pathways. In contrast, our results demonstrate that isoflavones are ERα agonists and ERβ agonists because they are at triggering transcriptional activation or repression with ERβ. The is isoflavones elicit distinct transcriptional actions from estrogens the they both to the binding of ERα and ERβ A.M. T. L. Greene Gustafsson J.A. M. 1997; PubMed Scopus Google Scholar, D. L. Greene 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, A.M. T. J. Gustafsson J.A. M. J. 1999; PubMed Scopus Google is that isoflavones to ERβ more effectively than to ERα. In ERβ has a greater affinity for genistein compared with ERα T. Carlsson B. Nilsson Y. Enmark E. Gustafsson J. Nilsson S. Mol. Pharmacol. 1998; 54: 105-112Crossref PubMed Scopus (723) Google Scholar). However, this in binding affinity is to for the distinct transcriptional actions of isoflavones because we that isoflavones a more at triggering transcriptional activity with ERβ compared with ERα. Furthermore, at genistein at activation of with ERα and recruiting to ERα, compared with ERβ. studies that the transcriptional actions of estrogens and isoflavones also from in their to coregulators and trigger transcriptional of ERα or ERβ. data are with the that proteins R.B. 1999; PubMed Scopus Google Scholar, 2000; PubMed Google Scholar) are for both transcriptional activation and repression by J. P. Gustafsson J.A. Leitman Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus (180) Google Scholar, M.M. J. K. G. R. K. J.A. Recent Prog. Horm. Res. 2000; 55: Google Scholar, C.M. 2000; PubMed Scopus Google Scholar). E2 coregulators to ERα and ERβ, whereas isoflavones selectively coregulators to ERβ. recruiting coregulators such as to both triggers transcriptional activation and repression pathways for both ERα and ERβ. E2 its of and effects by triggering transcriptional pathways of In contrast, at physiological S. J. L. M. Exp. Med. Biol. 1996; PubMed Scopus Google Scholar) genistein is at recruiting to ERα, it is at recruiting to ERβ. selectively recruiting coregulators to ERβ, isoflavones trigger ERβ-mediated transcriptional pathways. results suggest that isoflavones be at the clinical effects that are by ERβ not ERα. Moreover, isoflavones are more at triggering transcriptional repression compared with results that it may be to transcriptional activation or estrogens for HRT. is genistein more effectively to ERβ than to ERα. However, the binding of may the more effectively than the because the binding of coregulators has been to the of of an agonist from the J.A. Mol. Endocrinol. 1999; PubMed Google Scholar). The of of and the repression of ERβ-mediated by isoflavones may for the low incidence of menopausal symptoms, osteoporosis, cardiovascular disease, and breast and endometrial cancer in Asian (19Ingram D. Sanders K. Kolybaba M. Lopez D. Lancet. 1997; 350: 990-994Abstract Full Text Full Text PDF PubMed Scopus (681) Google H. Baillieres Clin. Endocrinol. Metab. 1998; 12: 605-623Abstract Full Text PDF PubMed Scopus (223) Google Scholar, 22Murkies A. Wilcox G. Davis S. J. Clin. Endocrinol. Metab. 1998; 83: 297-303Crossref PubMed Scopus (465) Google Scholar, 23Tham D. Gardner C. Haskell W. J. Clin. Endocrinol. Metab. 1998; 83: 2223-2235Crossref PubMed Scopus (746) Google Scholar, 24Davis S.R. Dalais F.S. Simpson E.R. Murkies A.L. Recent Prog. Horm. Res. 1999; 54: 185-210PubMed Google Scholar). our studies suggest that ERβ-mediated repression of the may be an important mechanism whereby isoflavones may prevent osteoporosis because of is to to osteoporosis R. J. Res. 1996; PubMed Scopus Google Scholar). also in ERβ S. H. E. M. L. E. Gustafsson J. P. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). have also that a of of breast cancer ERα this because these ERα. Furthermore, it is that ERα the effects on endometrial because these not ERβ A.H. F. J. Mol. Endocrinol. 2000; 24: PubMed Scopus Google Scholar). on these we that ERβ-selective estrogens such as isoflavones may prevent some menopausal symptoms and be to elicit effects on breast and endometrial compared with estrogens in HRT regimens that also trigger pathways. Consistent with this are the that soy protein relieves menopausal symptoms (30Albertazzi P. Pansini F. Bonaccorsi G. Zanotti L. Forini E. De Aloysio D. Obstet. Gynecol. 1998; 91: 6-11Crossref PubMed Scopus (441) Google Scholar, R. L. M. C.A. 2000; 7: PubMed Scopus Google Scholar) does not effects on the in postmenopausal women R. L. M. C.A. 2000; 7: PubMed Scopus Google Scholar, A.M. X. J. J. Clin. Endocrinol. Metab. 1999; PubMed Scopus Google Scholar). Furthermore, soy protein does not induce in endometrial and mammary in postmenopausal D. Cline Am. J. Clin. Nutr. 1998; 68 Suppl. 6: Scopus Google Scholar). natural estrogens and SERMs elicit selective clinical effects is a to the of safer estrogens for HRT. have that isoflavones elicit distinct transcriptional actions from estrogens by selectively recruiting coregulators to ERβ. data are with the that of the surface in a different genistein is to ERβ A.M. T. J. Gustafsson J.A. M. J. 1999; PubMed Scopus Google Scholar) compared with ERα A.M. T. L. Greene Gustafsson J.A. M. 1997; PubMed Scopus Google Scholar) or ERβ A.M. T. J. Gustafsson J.A. M. J. 1999; PubMed Scopus Google Scholar). Our results suggest that isoflavones may act as natural which may be safer than estrogens in HRT regimens because they selectively trigger the transcriptional pathways of ERβ. Estrogens in HRT also trigger ERα transcriptional which may the of breast and endometrial P. and M. Stallcup for and and for of the