Specific and redundant activities of ETV1 and ETV4 in prostate cancer aggressiveness revealed by co-overexpression cellular contexts

// Diana Mesquita 1 , Joao D. Barros-Silva 1 , Joana Santos 1 , Rolf I. Skotheim 2, 3 , Ragnhild A. Lothe 2, 3 , Paula Paulo 1, 2, 3 and Manuel R. Teixeira 1, 3, 4 1 Department of Genetics and Cancer Genetics Group – CI-IPOP, Portuguese Oncology Institute, Porto, Portugal 2 Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo, Norway 3 Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway 4 Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Portugal Correspondence to: Manuel R. Teixeira, e-mail: manuel.teixeira@ipoporto.min-saude.pt Keywords: prostate cancer, ETV1 and ETV4 co-overexpression, target genes, oncogenic role, PEA3-positive tumors Received: July 25, 2014      Accepted: December 5, 2014      Published: February 14, 2015 ABSTRACT Genomic rearrangements involving ETS transcription factors are found in 50–70% of prostate carcinomas. While the large majority of the rearrangements involve ERG , around 10% involve members of the PEA3 subfamily ( ETV1 , ETV4 and ETV5 ). Using a panel of prostate cancer cell lines we found co-overexpression of ETV1 and ETV4 in two cell line models of advanced prostate cancer (MDA-PCa-2b and PC3) and questioned whether these PEA3 family members would cooperate in the acquisition of oncogenic properties or show functional redundancy. Using shRNAs we found that ETV1 and ETV4 have partially overlapping functions, with ETV1 being more relevant for cell invasion and ETV4 for anchorage-independent growth. In vitro expression signatures revealed the regulation of both specific and shared candidate targets that may resemble cellular mechanisms in vivo by interaction with the same intermediate partners. By combining the phenotypic impact data and the gene expression profiles of in vitro models with clinico-pathological features and gene expression profiles of ETS-subtyped tumors, we identified a set of eight genes associated with advanced stage and a set of three genes associated with higher Gleason score, supporting an oncogenic role of ETV1 and ETV4 overexpression and revealing gene sets that may be useful as prognostic markers.