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Estrogen Receptor ß2 Negatively Regulates the Transactivation of Estrogen Receptor in Human Breast Cancer Cells

¹ Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden; ² Department of Pharmacology, University of Toronto, Toronto, Canada; ³ Department of Proteomics, School of Biotechnology, AlbaNova University Center, KTH-Royal Institute of Technology, Stockholm, Sweden; and ⁴ Cancer Research UK Labs and Section of Cancer Cell Biology, Department of Oncology, Imperial College London, London, United Kingdom

Requests for reprints: Chunyan Zhao, Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 57 Huddinge, Sweden. Phone: 46-8-6089273; Fax: 46-8-7745538; E-mail: chunyan.zhao{at}cnt.ki.se.

Estrogens, by binding to and activating two estrogen receptors (ER and ERß), are critically involved in the development of the mammary gland and breast cancer. An isoform of ERß, ERß2 (also called ERßcx), with an altered COOH-terminal region, is coexpressed with ER in many human breast cancers. In this study, we generated a stable cell line from MCF7 breast cancer cells expressing an inducible version of ERß2, along with endogenous ER, and examined the effects of ERß2 on the ER protein levels and function. We showed that ERß2 inhibited ER-mediated transactivation via estrogen response element and activator protein-1 sites of reporter constructs as well as the endogenous genes pS2 and MMP-1. Chromatin immunoprecipitation assays revealed that ERß2 expression caused a significant reduction in the recruitment of ER to both the pS2 and MMP-1 promoters. Furthermore, ERß2 expression induced proteasome-dependent degradation of ER. The inhibitory effects of ERß2 on ER activity were further confirmed in HEK293 cells that lack functional endogenous ERs. We also showed that ERß2 can interact with ER both in vitro and in mammalian cells, which is compatible with a model where ERß2/ER heterodimers are targeted to the proteasome. Finally, in human breast cancer samples, we observed that expression of ERß2 significantly correlated with ER-negative phenotype. Our data suggest that ERß2 could influence ER-mediated effects relevant for breast cancer development, including hormone responsiveness. [Cancer Res 2007;67(8):3955–62]

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