Estrogen Receptor (ER) β Regulates ERα Expression in Stromal Cells Derived from Ovarian Endometriosis

Context: Estradiol and its nuclear receptors, estrogen receptor (ER) alpha and ER beta, play critical roles in endometrium and endometriosis. Levels of ER beta, due to pathological hypomethylation of its promoter, are significantly higher in endometriotic vs. endometrial tissue and stromal cells, whereas ER alpha levels are lower in endometriosis. Estradiol regulates ER alpha gene expression via its alternatively used promoters A, B, and C. Objective: The aim of the study was to determine whether high levels of ER beta in endometriotic stromal cells from ovarian endometriomas regulate ER alpha gene expression. Results: ER beta knockdown significantly increased ER alpha mRNA and protein levels in endometriotic stromal cells. Conversely, ER beta overexpression in endometrial stromal cells decreased ER alpha mRNA and protein levels. ER beta knockdown significantly decreased proliferation of endometriotic stromal cells. Chromatin immunoprecipitation assays demonstrated that estradiol enhanced ER beta binding to nonclassical activator protein 1 and specificity protein 1 motifs in the ER alpha gene promoters A and C and a classic estrogen response element in promoter B in endometriotic stromal cells. Conclusions: High levels of ER beta suppress ER alpha expression and response to estradiol in endometrial and endometriotic stromal cells via binding to classic and nonclassic DNA motifs in alternatively used ER alpha promoters. ER beta also regulates cell cycle progression and might contribute to proliferation of endometriotic stromal cells. We speculate that a significantly increased ratio of ER beta: ER alpha in endometriotic tissues may also suppress progesterone receptor expression and contribute to progesterone resistance. Thus, ER beta may serve as a significant therapeutic target for endometriosis. (J Clin Endocrinol Metab 94: 615-622, 2009)