title: Global gene repression by the steroid receptor coactivator SRC-1 promotes oncogenesis.
abstract: Transcriptional control is the major determinant of cell fate. The steroid receptor coactivator (SRC)-1 enhances the activity of the estrogen receptor in breast cancer cells, where it confers cell survival benefits. Here, we report that a global analysis of SRC-1 target genes suggested that SRC-1 also mediates transcriptional repression in breast cancer cells. Combined SRC-1 and HOXC11 ChIPseq analysis identified the differentiation marker, CD24, and the apoptotic protein, PAWR, as direct SRC-1/HOXC11 suppression targets. Reduced expression of both CD24 and PAWR was associated with disease progression in patients with breast cancer, and their expression was suppressed in metastatic tissues. Investigations in endocrine-resistant breast cancer cell lines and SRC-1(-/-)/PyMT mice confirmed a role for SRC-1 and HOXC11 in downregulation of CD24 and PAWR. Through bioinformatic analysis and liquid chromatography/mass spectrometry, we identified AP1 proteins and Jumonji domain containing 2C (JMD2C/KDM4C), respectively, as members of the SRC-1 interactome responsible for transcriptional repression. Our findings deepen the understanding of how SRC-1 controls transcription in breast cancers.
authors.affiliation: Authors' Affiliations: Endocrine Oncology Research, Royal College of Surgeons in Ireland; UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland; and Department of Molecular and Cellular Biology and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Walsh
authors.forename: Jarlath C
authors.initials: JC
authors.lastname: Bolger
authors.forename: Christopher
authors.initials: C
authors.lastname: Byrne
authors.forename: Sinead
authors.initials: S
authors.lastname: Cocchiglia
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hao
authors.forename: Ailis
authors.initials: A
authors.lastname: Fagan
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.forename: Aoife
authors.initials: A
authors.lastname: Cahalin
authors.forename: Damian
authors.initials: D
authors.lastname: McCartan
authors.forename: Marie
authors.initials: M
authors.lastname: McIlroy
authors.forename: Peadar
authors.initials: P
authors.lastname: O'Gaora
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Arnold D
authors.initials: AD
authors.lastname: Hill
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Young
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D051379:Mice; D018345:Mice, Knockout; D056920:Nuclear Receptor Coactivator 1 / Q000502:physiology*; D011401:Promoter Regions, Genetic
chemical_list: D051017:Apoptosis Regulatory Proteins; D051927:CD24 Antigen; C497889:CD24 protein, human; C484731:HOXC11 protein, human; D018398:Homeodomain Proteins; C413655:KDM4C protein, human; C101296:prostate apoptosis response-4 protein; D056484:Jumonji Domain-Containing Histone Demethylases; D056920:Nuclear Receptor Coactivator 1