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Progesterone Receptor B Recruits a Repressor Complex to a Half-PRE Site of the Estrogen Receptor Gene Promoter

Department of Pharmaco-Biology (F.D., S.Z., R.M.), and Cellular Biology (M.L.P., F.G., L.M., S.A.) University of Calabria, Rende (Cosenza) Italy; Lester and Sue Smith Breast Center (I.B., S.A.W.F.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Professor Sebastiano Andò M.D., Department of Cellular Biology, University of Calabria, 87036 Rende (CS), Italy. E-mail: sebastiano.ando{at}unical.it.

In the present study, we demonstrate that elevated levels of the progesterone receptor (PR)-B isoform in breast cancer cells induces down-regulation of estrogen receptor (ER) mRNA and protein content, causing concomitant repression of the estrogen-regulated genes insulin receptor substrate 1, cyclin D1, and pS2, addressing a specific effect of PR/PR-B on ER gene transcription. ER gene promoter activity was drastically inhibited by PR-B overexpression. Promoter analysis revealed a transcriptionally responsive region containing a half-progesterone response element (PRE) site located at –1757 bp to –1752 bp. Mutation of the half-PRE down-regulated the effect induced by PR/PR-B overexpression. Moreover chromatin immunoprecipitation analyses revealed an increase of PR bound to the ER-regulatory region encompassing the half-PRE site, and the recruitment of a corepressor complex containing nuclear receptor corepressor (NCoR) but not silencing mediator of retinoid and thyroid hormone receptor and DAX1, concomitantly with hypoacetylation of histone H4 and displacement of RNA polymerase II. Furthermore, NCoR ablation studies demonstrated the crucial involvement of NCoR in the down-regulatory effects due to PR-B overexpression on ER protein and mRNA. We also demonstrated that the ER regulation observed in MCF-7 cells depended on PR-B expression because PR-B knockdown partially abrogates the feedback inhibition of ER levels after estrogenic stimulus. Our study provides evidence for a mechanism by which overexpressed PR-B is able to actively repress ER gene expression.

NURSA Molecule Pages Link:

Nuclear Receptors:   PR

Coregulators:   NCoR

Ligands:   17β-Estradiol  |  Progesterone  |  RU486

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