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

Elena Trukhacheva, Zhihong Lin, Scott Reierstad, You-Hong Cheng, Magdy P. Milad, Magdy Milad, Serdar E Bulun
The Journal of clinical endocrinology and metabolism · 2008 · vol. 94(2) , pp. 615–622 · doi:10.1210/jc.2008-1466 · PMID:19001520 · PMC2646522 · W2057291577
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High ERβ levels in endometriotic stromal cells suppress ERα expression and estradiol response by binding to ERα gene promoters, while ERβ knockdown reduces cell proliferation.

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Abstract

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

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Estrogen Receptor alpha Estrogen Receptor beta Ovarian Diseases Stromal Cells Adult Cell Cycle Cell Cycle Cell Cycle Cells, Cultured Endometriosis Endometriosis Endometriosis Estradiol Estradiol Estrogen Receptor alpha Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptor beta Estrogen Receptor beta

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