Trukhacheva Elena, Lin Zhihong, Reierstad Scott, Cheng You-Hong, Milad Magdy, Bulun Serdar E
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, 303 East Superior Street, 4-123, Chicago, Illinois 60611, USA.
J Clin Endocrinol Metab. 2009 Feb;94(2):615-22. doi: 10.1210/jc.2008-1466. Epub 2008 Nov 11.
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.
The aim of the study was to determine whether high levels of ERbeta in endometriotic stromal cells from ovarian endometriomas regulate ERalpha gene expression.
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.
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.
雌二醇及其核受体，雌激素受体（ER）α和ERβ，在子宫内膜和子宫内膜异位症中发挥关键作用。由于其启动子的病理性低甲基化，ERβ水平在子宫内膜异位组织与子宫内膜组织及基质细胞中显著更高，而ERα水平在子宫内膜异位症中较低。雌二醇通过其交替使用的启动子A、B和C调节ERα基因表达。
本研究的目的是确定来自卵巢子宫内膜异位囊肿的子宫内膜异位基质细胞中高水平的ERβ是否调节ERα基因表达。
ERβ敲低显著增加子宫内膜异位基质细胞中ERα mRNA和蛋白水平。相反，子宫内膜基质细胞中ERβ过表达降低ERα mRNA和蛋白水平。ERβ敲低显著降低子宫内膜异位基质细胞的增殖。染色质免疫沉淀试验表明，雌二醇增强了ERβ与子宫内膜异位基质细胞中ERα基因启动子A和C中的非经典激活蛋白1和特异性蛋白1基序以及启动子B中的经典雌激素反应元件的结合。
高水平的ERβ通过与交替使用的ERα启动子中的经典和非经典DNA基序结合，抑制子宫内膜和子宫内膜异位基质细胞中ERα的表达及对雌二醇的反应。ERβ还调节细胞周期进程，并可能促进子宫内膜异位基质细胞的增殖。我们推测，子宫内膜异位组织中ERβ:ERα比例的显著增加也可能抑制孕激素受体表达并导致孕激素抵抗。因此，ERβ可能是子宫内膜异位症的一个重要治疗靶点。
