Progesterone Receptor B recruits a repressor complex to a half-PRE site of the Estrogen Receptor alfa gene promoter

In the present study, we demonstrate that elevated levels of the progesterone receptor (PR)-B isoformin breast cancer cells induces down-regulation of estrogen receptor (ER) mRNAand protein content,causing concomitant repression of the estrogen-regulated genes insulin receptor substrate 1, cyclinD1, and pS2, addressing a specific effect of PR/PR-B on ER gene transcription. ER gene promoteractivity was drastically inhibited by PR-B overexpression. Promoter analysis revealed a transcriptionallyresponsive region containing a half-progesterone response element (PRE) site located at1757 bp to1752 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 complexcontaining nuclear receptor corepressor (NCoR) but not silencing mediator of retinoid and thyroidhormone receptor and DAX1, concomitantly with hypoacetylation of histone H4 and displacement ofRNA polymerase II. Furthermore, NCoR ablation studies demonstrated the crucial involvement ofNCoR in the down-regulatory effects due to PR-B overexpression on ER protein and mRNA. We alsodemonstrated that the ER regulation observed in MCF-7 cells depended on PR-B expression becausePR-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 repressER gene expression.