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J. Biol. Chem., Vol. 283, Issue 11, 6752-6763, March 14, 2008

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Estrogen Induces Estrogen-related Receptor Gene Expression and Chromatin Structural Changes in Estrogen Receptor (ER)-positive and ER-negative Breast Cancer Cells^*

Peng Hu, H. Karimi Kinyamu, Liangli Wang, Jessica Martin, Trevor K. Archer, and Christina Teng¹

From the Gene Regulation Section, Laboratory of Reproductive and Developmental Toxicology and Chromatin and Gene Expression Section, Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

Estrogen-related receptor (ERR), a member of the nuclear receptor superfamily, is closely related to the estrogen receptors (ER and ERβ). The ERR gene is estrogen-responsive in several mouse tissues and cell lines, and a multiple hormone-response element (MHRE) in the promoter is an important regulatory region for estrogen-induced ERR gene expression. ERR was recently shown to be a negative prognostic factor for breast cancer survival, with its expression being highest in cancer cells lacking functional ER. The contribution of ERR in breast cancer progression remains unknown but may have important clinical implications. In this study, we investigated ERR gene expression and chromatin structural changes under the influence of 17β-estradiol in both ER-positive MCF-7 and ER-negative SKBR3 breast cancer cells. We mapped the nucleosome positions of the ERR promoter around the MHRE region and found that the MHRE resides within a single nucleosome. Local chromatin structure of the MHRE exhibited increased restriction enzyme hypersensitivity and enhanced histone H3 and H4 acetylation upon estrogen treatment. Interestingly, estrogen-induced chromatin structural changes could be repressed by estrogen antagonist ICI 182 780 in MCF-7 cells yet were enhanced in SKBR3 cells. We demonstrated, using chromatin immunoprecipitation assays, that 17β-estradiol induces ERR gene expression in MCF-7 cells through active recruitment of co-activators and release of co-repressors when ERR and AP1 bind and ER is tethered to the MHRE. We also found that this estrogen effect requires the MAPK signaling pathway in both cell lines.

Received for publication, July 19, 2007 , and in revised form, December 6, 2007.

^* This work was supported by the intramural research program of the National Institutes of Health, NIEHS. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Gene Regulation Section, Laboratory of Reproductive and Developmental Toxicology, NIEHS, National Institutes of Health, 111 Alexander Dr., P. O. Box 12233, MD E2-01, Research Triangle Park, NC 27709. Tel.: 919-541-0344; Fax: 919-5412-1978; E-mail: teng1{at}niehs.nih.gov.

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