title: Estrogen-related receptor alpha expression and function is associated with the transcriptional coregulator AIB1 in breast carcinoma.
abstract: The significance of the estrogen-related receptor alpha (ERRalpha) as prognostic marker for poor clinical outcome in breast carcinoma has recently been reported. Transcriptional activity of nuclear receptors such as ERRalpha 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 ERRalpha 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 ERRalpha only in tumors, where estrogen receptor (ERalpha) expression was low or absent. In ERalpha high expressing tumors, no correlation of ERRalpha and pS2 was observed. AIB1 interacts directly with ERRalpha as shown by fluorescence-resonance energy transfer, mammalian two-hybrid, and coimmunoprecipitation assays with endogenous proteins. It enhances ERRalpha transcriptional activity in ERalpha-negative breast cancer cell lines as shown in functional reporter gene assays. Blocking ERRalpha with an inverse agonist abolished interaction and coactivation by AIB1. Recruitment of both proteins to ERRalpha target gene promoters further supports the significance of their interaction. Our findings identify AIB1 as functionally relevant cofactor for ERRalpha in breast carcinoma. ERRalpha/AIB1 complexes may control estradiol-regulated genes in a hormone-independent manner. Accordingly, ERRalpha might be a rewarding target for treatment of endocrine-resistant tumors.
authors.affiliation: German Cancer Research Center (DKFZ), Division of Molecular Genetics, Heidelberg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heck
authors.forename: Joachim
authors.initials: J
authors.lastname: Rom
authors.forename: Verena
authors.initials: V
authors.lastname: Thewes
authors.forename: Natalia
authors.initials: N
authors.lastname: Becker
authors.forename: Beatrix
authors.initials: B
authors.lastname: Blume
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Sinn
authors.forename: Ulrich
authors.initials: U
authors.lastname: Deuschle
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D031541:Fluorescence Resonance Energy Transfer; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D056921:Nuclear Receptor Coactivator 3; D012333:RNA, Messenger / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D051548:Histone Acetyltransferases; D056921:Nuclear Receptor Coactivator 3; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D015534:Trans-Activators; D000097983:ERRalpha Estrogen-Related Receptor; C538866:NCOA3 protein, human