Negative Regulation of Estrogen Signaling by ERß and RIP140 in Ovarian Cancer Cells.

Molecular endocrinology (Baltimore, Md.)

PubMedID: 23885094

Docquier A, Garcia A, Savatier J, Boulahtouf A, Bonnet S, Bellet V, Busson M, Margeat E, Jalaguier S, Royer C, Balaguer P, Cavaillès V. Negative Regulation of Estrogen Signaling by ERß and RIP140 in Ovarian Cancer Cells. Mol Endocrinol. 2013;27(9):1429-41.
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 ERß ectopic expression on 17ß-estradiol (E2)-induced transactivation and cell proliferation in ERa-positive BG1 ovarian cancer cells. As expected, ERß 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 ERa-selective ligand propyl pyrazole triol was less marked than with the pan-agonist (E2) or the ERß-selective (8ß-vinyl-estradiol) ligands, indicating that ERß activation reinforced the inhibitory effects of ERß. Interestingly, in E2-stimulated BG1 cells, ERß was more efficient than ERa to regulate the expression of receptor-interacting protein 140 (RIP140), a major ERa transcriptional corepressor. In addition, we found that the RIP140 protein interacted better with ERß than with ERa (both in vitro and in intact cells by fluorescence cross-correlation spectroscopy). Moreover, RIP140 recruitment on the stably integrated reporter ERE was increased upon ERß overexpression, and ERß activity was more sensitive to repression by RIP140. Finally, small interfering RNA-mediated knockdown of RIP140 expression abolished the repressive effect exerted by activated ERß on the regulation of ERE-controlled transcription by estrogens. Altogether, these data demonstrate the inhibitory effects of ERß on estrogen signaling in ovarian cancer cells and the key role that RIP140 plays in this phenomenon.