A gene signature identified using a mouse model of androgen receptor-dependent prostate cancer predicts biochemical relapse in human disease Vanessa C. Thompson 1 *, Tanya K. Day 1 *, Tina Bianco-Miotto 1 , Luke A. Selth 1,2 , Guangzhou Han 3 , Mervyn Thomas 4 , Grant Buchanan 1,2,5 , Howard I. Scher 6 , Colleen C. Nelson 7 , the Australian Prostate Cancer BioResource 8 , Norman M. Greenberg 3 , Lisa M. Butler 1,2 and Wayne D. Tilley 1,2 1 Dame Roma Mitchell Cancer Research Laboratories and Adelaide Prostate Cancer Research Centre, Discipline of Medicine, University of Adelaide, Hanson Institute, Adelaide, South Australia, Australia 2 Freemasons Foundation Centre for Men’s Health, University of Adelaide, South Australia, Australia 3 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 4 Emphron Informatics, Toowong, Queensland, Australia 5 Molecular Ageing Laboratory, The University of Adelaide, Adelaide, South Australia, Australia 6 Genitourinary Oncology Service, Sidney Kimmel Center for Urologic and Prostate Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY 7 The Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, and Level 1, Building 33, Princess Alexandra Hospital, 199 Ipswich Road, Brisbane, QLD, Australia 8 The Australian Prostate Cancer BioResource, Institute of Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia Mutations in the androgen receptor (AR) have been detected in experimental and clinical prostate tumors. Mice with enforced prostate-specific expression of one such receptor variant, AR-E231G, invariably develop prostatic intraepithelial neoplasia by 12 weeks and metastatic prostate cancer by 52 weeks. The aim of this study was to identify genes with altered expression in the prostates of AR-E231G mice at an early stage of disease that may act as drivers of AR-mediated tumorigenesis. The gene expression profile of AR-E231G prostate tissue from 12-week-old mice was compared to an equivalent profile from mice expressing the AR-T857A receptor variant (analogous to the AR-T877A variant in LNCaP cells), which do not develop prostate tumors. One hundred and thirty-two genes were differentially expressed in AR-E231G prostates. Classification of these genes revealed enrichment for cellular pathways known to be involved in prostate cancer, including cell cycle and lipid metabolism. Suppression of two genes upregulated in the AR-E231G model, ADM and CITED1, increased cell death and reduced proliferation of human prostate cancer cells. Many genes differentially expressed in AR-E231G prostates are also deregulated in human tumors. Three of these genes, ID4, NR2F1 and PTGDS, which were expressed at consistently lower levels in clinical prostate cancer compared to nonmalignant tissues, formed a signature that predicted biochemical relapse (hazard ratio 2.2, p 5 0.038). We believe that our findings support the value of this novel mouse model of prostate cancer to identify candidate therapeutic targets and/or biomarkers of human disease. Key words: androgen receptor, prostate cancer, mouse model, gene signature Abbreviations: ADT: androgen deprivation therapy; ANTS: AR-NTD signature sequence; APC BioResource: Australian Prostate Cancer BioResource; AR: androgen receptor; CRPC, castrate resistant prostate cancer; DHT: 5a-dihydrotestosterone; FBS: fetal bovine serum; HR, hazard ratio; MSKCC: Memorial Sloan-Kettering Cancer Center; NTD: amino terminal domain; PIN: prostatic intraepithelial neoplasia; qPCR: quantitative real time PCR; TRAMP: transgenic adenocarcinoma of the mouse prostate; wtAR: wild-type AR Additional Supporting Information may be found in the online version of this article. *V.C.T. and T.K.D. contributed equally to this work Grant sponsor: United States Department of Defense Prostate Cancer Research Program; Grant number: PC080400, W81XWH-07-1-0310; Grant sponsor: Prostate Cancer Foundation of Australia Grant; Grant numbers: YIG03, YI02, YI0810, 497244, EG0809; Grant sponsor: Cancer Australia; Grant number: 627229; Grant sponsors: EJ Whitten Foundation Fellowship, W Bruce Hall Cancer Council SA Research Fellowship, Freemason’s Foundation for Men’s Health; Grant sponsor: National Health and Medical Research Committee CDA Level 1 Fellowship; Grant number: 627018; Grant sponsor: Cancer Council South Australia Senior Research Fellowship, Grant sponsor: NHMRC; Grant numbers: 290456, 614296, 453662, 627185 DOI: 10.1002/ijc.26414 History: Received 30 Mar 2011; Accepted 23 Aug 2011; Online 7 Sep 2011 Correspondence to: Wayne D. Tilley, Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, University of Adelaide, Hanson Institute, P.O. Box 14, Rundle Mall, Adelaide, South Australia 5000, Australia, Fax: 61-8-8222-3217, E-mail: wayne.tilley@health.sa. gov.au. Early Detection and Diagnosis Int. J. Cancer: 131, 662–672 (2012) V C 2011 UICC International Journal of Cancer IJC