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Mol Endocrinol. 2014 Aug;28(8):1304-15. doi: 10.1210/me.2013-1421. Epub 2014 Jul 3.

ERβ- and prostaglandin E2-regulated pathways integrate cell proliferation via Ras-like and estrogen-regulated growth inhibitor in endometriosis.

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Division of Reproductive Biology Research (D.M., M.T.D., P.Y., J.S.C., A.N., S.S.M., M.O., C.M.E., M.E.P., E.S., S.E.B.), Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Northwestern University Biomedical Informatics Center (part of the Northwestern CTSA) and The Robert H. Lurie Comprehensive Cancer Center (G.F.), and Department of Pathology (J.J.W.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.


In endometriosis, stromal and epithelial cells from the endometrium form extrauterine lesions and persist in response to estrogen (E2) and prostaglandin E2 (PGE2). Stromal cells produce excessive quantities of estrogen and PGE2 in a feed-forward manner. However, it is unknown how estrogen stimulates cell proliferation and survival for the establishment and persistence of disease. Previous studies suggest that estrogen receptor-β (ERβ) is strikingly overexpressed in endometriotic stromal cells. Thus, we integrated genome-wide ERβ binding data from previously published studies in breast cells and gene expression profiles in human endometriosis and endometrial tissues (total sample number = 81) and identified Ras-like, estrogen-regulated, growth inhibitor (RERG) as an ERβ target. Estradiol potently induced RERG mRNA and protein levels in primary endometriotic stromal cells. Chromatin immunoprecipitation demonstrated E2-induced enrichment of ERβ at the RERG promoter region. PGE2 via protein kinase A phosphorylated RERG and enhanced the nuclear translocation of RERG. RERG induced the proliferation of primary endometriotic cells. Overall, we demonstrated that E2/ERβ and PGE2 integrate at RERG, leading to increased endometriotic cell proliferation and represents a novel candidate for therapeutic intervention.

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