Résumé
In hormone-dependent tissues such as breast and ovary, tumorigenesis is associated with an altered expression ratio between the two estrogen receptor (ER) subtypes. In this study, we investigated the effects of ER beta ectopic expression on 17 beta-estradiol (E2)-induced transactivation and cell proliferation in ER alpha-positive BG1 ovarian cancer cells. As expected, ER beta expression strongly decreased the mitogenic effect of E2, significantly reduced E2-dependent transcriptional responses (both on a stably integrated estrogen response element [ERE] reporter gene and on E2-induced mRNAs), and strongly enhanced the formation of ER heterodimers as evidenced by chromatin immunoprecipitation analysis. Inhibition by the ER alpha-selective ligand propyl pyrazole triol was less marked than with the pan-agonist (E2) or the ER alpha-selective (8 beta-vinyl-estradiol) ligands, indicating that ER beta activation reinforced the inhibitory effects of ER beta. Interestingly, in E2-stimulated BG1 cells, ER beta was more efficient than ER alpha to regulate the expression of receptor-interacting protein 140 (RIP140), a major ER alpha transcriptional corepressor. In addition, we found that the RIP140 protein interacted better with ER beta than with ER alpha (both in vitro and in intact cells by fluorescence cross-correlation spectroscopy). Moreover, RIP140 recruitment on the stably integrated reporter ERE was increased upon ER beta overexpression, and ER beta activity was more sensitive to repression by RIP140. Finally, small interfering RNA-mediated knockdown of RIP140 expression abolished the repressive effect exerted by activated ER beta on the regulation of ERE-controlled transcription by estrogens. Altogether, these data demonstrate the inhibitory effects of ER beta on estrogen signaling in ovarian cancer cells and the key role that RIP140 plays in this phenomenon.