Genistein-mediated attenuation of tamoxifen-induced antagonism from estrogen receptor-regulated genes

In this study we demonstrate that physiologic concentrations of genistein a re 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 co expression of CBP (the cAMP response element binding protein coactivator) s ynergistically increases this signal. Exogenous expression of a nuclear rec eptor corepressor (NCoR) was, however, unable to alter genistein-mediated t ransactivation. In in vitro binding assays, we show that genistein, but not 4-hydroxytamoxifen, induces a direct interaction between radiolabeled ER a lpha and a GST-SRC-1 fusion protein. More importantly, coincubation with ge nistein and 4-hydroxytamoxifen or genistein treatment following preincubati on of the ER with 4-hydroxytamoxifen also resulted in a strong physical int eraction with SRC-1. These findings imply that genistein-induced shifts in the coregulator status of ER alpha may be involved in transcriptional regul ation and suggest that tamoxifen-mediated antagonism at ER-dependent genes is sensitive to attenuation by low levels of genistein. (C) 1998 Academic P ress.