title: Negative regulation of estrogen signaling by ERβ and RIP140 in ovarian cancer cells.
abstract: 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 ERβ ectopic expression on 17β-estradiol (E2)-induced transactivation and cell proliferation in ERα-positive BG1 ovarian cancer cells. As expected, ERβ 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 ERα-selective ligand propyl pyrazole triol was less marked than with the pan-agonist (E2) or the ERβ-selective (8β-vinyl-estradiol) ligands, indicating that ERβ activation reinforced the inhibitory effects of ERβ. Interestingly, in E2-stimulated BG1 cells, ERβ was more efficient than ERα to regulate the expression of receptor-interacting protein 140 (RIP140), a major ERα transcriptional corepressor. In addition, we found that the RIP140 protein interacted better with ERβ than with ERα (both in vitro and in intact cells by fluorescence cross-correlation spectroscopy). Moreover, RIP140 recruitment on the stably integrated reporter ERE was increased upon ERβ overexpression, and ERβ activity was more sensitive to repression by RIP140. Finally, small interfering RNA-mediated knockdown of RIP140 expression abolished the repressive effect exerted by activated ERβ on the regulation of ERE-controlled transcription by estrogens. Altogether, these data demonstrate the inhibitory effects of ERβ on estrogen signaling in ovarian cancer cells and the key role that RIP140 plays in this phenomenon.
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, INSERM, U896, Montpellier F-34298, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Docquier
authors.forename: Aurélie
authors.initials: A
authors.lastname: Garcia
authors.forename: Julien
authors.initials: J
authors.lastname: Savatier
authors.forename: Abdel
authors.initials: A
authors.lastname: Boulahtouf
authors.forename: Sandrine
authors.initials: S
authors.lastname: Bonnet
authors.forename: Virginie
authors.initials: V
authors.lastname: Bellet
authors.forename: Muriel
authors.initials: M
authors.lastname: Busson
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Margeat
authors.forename: Stéphan
authors.initials: S
authors.lastname: Jalaguier
authors.forename: Cathy
authors.initials: C
authors.lastname: Royer
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.forename: Vincent
authors.initials: V
authors.lastname: Cavaillès
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D004273:DNA, Neoplasm / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D009687:Nuclear Proteins / Q000378:metabolism*; D000078723:Nuclear Receptor Interacting Protein 1; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding / Q000235:genetics; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D008024:Ligands; C000627127:NRIP1 protein, human; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1