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Molecular Endocrinology
Year: 2010  |  Volume: 24  |  Issue: 5  |  Page No.: 969 - 980

Regulation of ERR{alpha} Gene Expression by Estrogen Receptor Agonists and Antagonists in SKBR3 Breast Cancer Cells: Differential Molecular Mechanisms Mediated by G Protein-Coupled Receptor GPR30/GPER-1

Y Li, L Birnbaumer and C. T. Teng    

Abstract:

In selected tissues and cell lines, 17β-estradiol (E2) regulates the expression of estrogen-related receptor (ERR), a member of the orphan nuclear receptor family. This effect is thought to be mediated by the estrogen receptor (ER). However in the ER- and ERβ-negative SKBR3 breast cancer cell line, physiological levels of E2 also stimulate ERR expression. Here, we explored the molecular mechanism that mediates estrogen action in ER-negative breast cancer cells. We observed that E2, the ER agonist, as well as the ER antagonists ICI 182,780 and tamoxifen (TAM), a selective ER modulator, stimulate the transcriptional activity of the ERR gene and increase the production of ERR protein in SKBR3 cells. Moreover, the ERR downstream target genes expression and cellular proliferation are also increased. We show further that the G protein-coupled receptor GPR30/GPER-1 (GPER-1) mediates these effects. The GPER-1 specific ligand G-1 mimics the actions of E2, ICI 182,780, and TAM on ERR expression, and changing the levels of GPER-1 mRNA by overexpression or small interfering RNA knockdown affected the expression of ERR accordingly. Utilizing inhibitors, we delineate a different downstream pathway for ER agonist and ER antagonist-triggered signaling through GPER-1. We also find differential histone acetylation and transcription factor recruitment at distinct nucleosomes of the ERR promoter, depending on whether the cells are activated with E2 or with ER antagonists. These findings provide insight into the molecular mechanisms of GPER-1/ERR-mediated signaling and may be relevant to what happens in breast cancer cells escaping inhibitory control by TAM.

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