title: Genistein's "ER-dependent and independent" actions are mediated through ER pathways in ER-positive breast carcinoma cell lines.
abstract: Genistein, a natural flavone found in soy has been postulated to be responsible for lowering the rate of breast cancer in Asian women. Our previous studies have shown that genistein exerts multiple suppressive effects on both estrogen receptor positive (ER+) as well as estrogen receptor negative (ER-) human breast carcinoma lines suggesting that the mechanisms of these effects may be independent of ER pathways. In the present study however we provide evidence that in the ER+ MCF-7, T47D and 549 lines but not in the ER-MDA-MB-231 and MDA-MB-468 lines both presumed "ER-dependent" and "ER-independent" actions of genistein are mediated through ER pathways. Genistein's antiproliferative effects are estrogen dependent in these ER+ lines, being more pronounced in estrogen-containing media and in the presence of exogenous 17-beta estradiol. Genistein also inhibits the expression of ER-downstream genes including pS2 and TGF-beta in these ER+ lines and this inhibition is also dependent on the presence of estrogen. Genistein inhibits estrogen-induced protein tyrosine kinase (PTK) activity. Genistein is only a weak transcriptional activator and actually decreases ERE-CAT levels induced by 17-beta estradiol in the ER+ lines. Genistein also decreases steady state ER mRNA only in the presence of estrogen in the ER+ lines thereby manifesting another suppression of and through the ER pathway. Our observations resurrect the hypothesis that genistein functions as a "good estrogen" in ER+ breast carcinomas. Since chemopreventive effects of genistein would be targeted to normal ER-positive ductal-lobular cells of the breast, this "good estrogen" action of genistein is most relevant to our understanding of chemoprevention.
authors.affiliation: Department of Surgery, Shanghai Medical University, P. R. China.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Shao
authors.forename: Z Z
authors.initials: ZZ
authors.lastname: Shen
authors.forename: J A
authors.initials: JA
authors.lastname: Fontana
authors.forename: S H
authors.initials: SH
authors.lastname: Barsky
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011506:Proteins; D011960:Receptors, Estrogen / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D020218:Response Elements; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D025521:Tumor Suppressor Proteins
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; D011506:Proteins; D011960:Receptors, Estrogen; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D019833:Genistein; D011505:Protein-Tyrosine Kinases