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

Division of Reproductive Biology Research (E.T., Z.L., S.R., Y.-H.C., S.E.B.), and Division of Reproductive Endocrinology and Infertility (E.T., M.M., S.E.B.), Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Serdar E. Bulun, M.D., Professor and Chief, Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, 303 East Superior Street, 4-123, Chicago, Illinois 60611. E-mail: s-bulun{at}northwestern.edu.

Context: Estradiol and its nuclear receptors, estrogen receptor (ER) and ERβ, play critical roles in endometrium and endometriosis. Levels of ERβ, due to pathological hypomethylation of its promoter, are significantly higher in endometriotic vs. endometrial tissue and stromal cells, whereas ER levels are lower in endometriosis. Estradiol regulates ER gene expression via its alternatively used promoters A, B, and C.

Objective: The aim of the study was to determine whether high levels of ERβ in endometriotic stromal cells from ovarian endometriomas regulate ER gene expression.

Results: ERβ knockdown significantly increased ER mRNA and protein levels in endometriotic stromal cells. Conversely, ERβ overexpression in endometrial stromal cells decreased ER mRNA and protein levels. ERβ knockdown significantly decreased proliferation of endometriotic stromal cells. Chromatin immunoprecipitation assays demonstrated that estradiol enhanced ERβ binding to nonclassical activator protein 1 and specificity protein 1 motifs in the ER gene promoters A and C and a classic estrogen response element in promoter B in endometriotic stromal cells.

Conclusions: High levels of ERβ suppress ER expression and response to estradiol in endometrial and endometriotic stromal cells via binding to classic and nonclassic DNA motifs in alternatively used ER promoters. ERβ also regulates cell cycle progression and might contribute to proliferation of endometriotic stromal cells. We speculate that a significantly increased ratio of ERβ:ER in endometriotic tissues may also suppress progesterone receptor expression and contribute to progesterone resistance. Thus, ERβ may serve as a significant therapeutic target for endometriosis.