Genomewide Search of Oncogenic Pathways Cooperating With ETS Fusions in Prostate Cancer

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 three-year grant period, we found that 1 Tmprss2-ETS fusions cooperate with Pten-loss, but not with Nkx3.1-loss, to promote development of localized prostate cancer. 2 Genes deleted in the interstitial region between Tmprss2 and Erg cooperate with Pten-loss, or Pten-loss plus ectopic Tmprss2-Erg expression at the early stage, leading to development of invasive prostate cancer with features of epithelial-mesenchymal transition. We identified several interstitial genes, including ETS2, HMGN1 and BACE2, as candidate tumor suppressors and confirmed that loss of one copy of Ets2 was sufficient for prostate cancer progression under a Pten-null background. 3 Another ETS family TF, ETV6, which is deleted in some prostate cancer cases including TMPRSS2-ERG fusion positive case, is also a tumor suppressor in prostate cancer and it may contribute to prostate tumorigenesis via the PRC2 complex thus similar to ERG. Overall, our work has unveiled several oncogenic pathways due to loss of tumor suppressors in prostate cancer under the context of TMPRSS2-ETS gene fusions.