Genistein-mediated attenuation of tamoxifen-induced antagonism from estrogen receptor-regulated genes.
In this study we demonstrate that physiologic concentrations of genistein are sufficient to mediate agonism and to reverse the repressive effects of 4-hydroxytamoxifen on estrogen receptor (ER alpha)-responsive reporter genes. We also show that overexpression of the steroid receptor coactivator (SRC-1) potentiates transactivation by genistein-activated ER alpha and that coexpression of CBP (the cAMP response element binding protein coactivator) synergistically increases this signal. Exogenous expression of a nuclear receptor corepressor (NCoR) was, however, unable to alter genistein-mediated transactivation. In in vitro binding assays, we show that genistein, but not 4-hydroxytamoxifen, induces a direct interaction between radiolabeled ER alpha and a GST-SRC-1 fusion protein. More importantly, coincubation with genistein and 4-hydroxytamoxifen or genistein treatment following preincubation of the ER with 4-hydroxytamoxifen also resulted in a strong physical interaction with SRC-1. These findings imply that genistein-induced shifts in the coregulator status of ER alpha may be involved in transcriptional regulation and suggest that tamoxifen-mediated antagonism at ER-dependent genes is sensitive to attenuation by low levels of genistein.
Schwartz
J A
JA
Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA. jschwart@med.wayne.edu
Liu
G
G
Brooks
S C
SC
D004357:Drug Synergism; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D005786:Gene Expression Regulation / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000235:genetics; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D056920:Nuclear Receptor Coactivator 1; D011960:Receptors, Estrogen / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D019833:Genistein; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D005982:Glutathione Transferase