Estrogen-Related Receptor Expression and Function Is Associated with the Transcriptional Coregulator AIB1 in Breast Carcinoma

¹German Cancer Research Center (DKFZ), Division of Molecular Genetics; Departments of ²Gynecology and Obstetrics and ³Pathology, University of Heidelberg, Heidelberg, Germany; and ⁴Phenex Pharmaceuticals AG, Ludwigshafen, Germany

^* To whom correspondence should be addressed. E-mail: m.macleod{at}dkfz.de.

	Abstract

The significance of the estrogen-related receptor (ERR) as prognostic marker for poor clinical outcome in breast carcinoma has recently been reported. Transcriptional activity of nuclear receptors such as ERR depends on coregulatory proteins. Thus, we compared the expression of different receptors, coregulators, and target genes on RNA and protein level in identical primary breast tumor samples (n = 48). We found a positive correlation between the transcripts of ERR and AIB1 (amplified in breast cancer-1), a coactivator overexpressed in breast cancers and associated with resistance to antihormone treatment. These data were confirmed on protein level, studying an independent patient collection (n = 257). Expression of the estrogen-regulated gene pS2 was associated with ERR only in tumors, where estrogen receptor (ER) expression was low or absent. In ER high expressing tumors, no correlation of ERR and pS2 was observed. AIB1 interacts directly with ERR as shown by fluorescence-resonance energy transfer, mammalian two-hybrid, and coimmunoprecipitation assays with endogenous proteins. It enhances ERR transcriptional activity in ER-negative breast cancer cell lines as shown in functional reporter gene assays. Blocking ERR with an inverse agonist abolished interaction and coactivation by AIB1. Recruitment of both proteins to ERR target gene promoters further supports the significance of their interaction. Our findings identify AIB1 as functionally relevant cofactor for ERR in breast carcinoma. ERR/AIB1 complexes may control estradiol-regulated genes in a hormone-independent manner. Accordingly, ERR might be a rewarding target for treatment of endocrine-resistant tumors. [Cancer Res 2009;69(12):5186–93]

Key Words: Estrogen-related receptor, Estrogen receptor, breast cancer, Amplified in breast cancer-1, coregulator