title: The ETS family member GABPα modulates androgen receptor signalling and mediates an aggressive phenotype in prostate cancer.
abstract: In prostate cancer (PC), the androgen receptor (AR) is a key transcription factor at all disease stages, including the advanced stage of castrate-resistant prostate cancer (CRPC). In the present study, we show that GABPα, an ETS factor that is up-regulated in PC, is an AR-interacting transcription factor. Expression of GABPα enables PC cell lines to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. GABPα has a transcriptional role that dissects the overlapping cistromes of the two most common ETS gene fusions in PC: overlapping significantly with ETV1 but not with ERG target genes. GABPα bound predominantly to gene promoters, regulated the expression of one-third of AR target genes and modulated sensitivity to AR antagonists in hormone responsive and castrate resistant PC models. This study supports a critical role for GABPα in CRPC and reveals potential targets for therapeutic intervention.
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK Department of Urology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Sharma
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Charlie E
authors.initials: CE
authors.lastname: Massie
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Butter
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Helene
authors.initials: H
authors.lastname: Bon
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramos-Montoya
authors.affiliation: Department of Bioinformatics, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Suraj
authors.initials: S
authors.lastname: Menon
authors.affiliation: Department of Bioinformatics, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Rory
authors.initials: R
authors.lastname: Stark
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Lamb
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Scott
authors.affiliation: Department of Pathology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Warren
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK Department of Urology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK den22@medschl.cam.ac.uk.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Gaustadalleen 21, Oslo N-0349, Norway Department of Cancer Prevention and Department of Urology, Oslo University Hospital, Oslo N-0349, Norway.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D051268:GA-Binding Protein Transcription Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D059002:Androgen Receptor Antagonists; D051268:GA-Binding Protein Transcription Factor; C495661:GABPA protein, human; D011944:Receptors, Androgen
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