Genome-wide Search of Oncogenic Pathways Cooperating with ETS Fusions in Prostate Cancer

Abstract

Abstract : Gene fusions involving ETS family transcription factors (TFs) (mainly ERG and ETV1) have been identified in 50% of prostate cancer cases. To address their roles in prostate cancer, we generated multiple Tmprss2-ETS knockin mouse models. The goal of this project is to identify oncogenic pathways cooperating with ETS fusions using these knockin models. During the second year, we continued our characterization of these knockin models. In addition to our previous observation that Tmprss2-ETS fusions cooperate with Pten-loss, but not with Nkx3.1-loss, to promote development of localized prostate cancer, we found that genes deleted in the interstitial region between Tmprss2 and Erg may cooperate with Pten-loss, or Pten-loss plus ectopic Tmprss2-Erg expression, leading to development of invasive prostate cancer. Furthermore, by focusing on another ETS family TF, ETV6, which is deleted in some prostate cancer cases (including TMPRSS2-ERG fusion positive case), we found that it is also a tumor suppressor in prostate cancer. Overall, the work we have performed so far has identified two additional oncogenic pathways induced by loss of genes in the Tmprss2/Erg interstitial region or by loss of ETV6 that may cooperate with Pten-loss or Tmprss2-Erg fusion plus Pten-loss, in leading to aggressive prostate cancer. Future work will focus on identification of tumor suppressor(s) in the interstitial region, oncogenic program driven by ETV6-loss, and identification of any additional Tmprss2-ETS-cooperating oncogenic pathways.