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Gene fusions involving ETS family transcription factors (mainly  TMPRSS2-ERG  and  TMPRSS2-ETV1  fusions) have been found in ~50% of human prostate cancer cases. Although expression of  TMPRSS2-ERG  or  TMPRSS2-ETV1  fusion alone is insufficient to initiate prostate tumorigenesis, they appear to sensitize prostate epithelial cells for cooperation with additional oncogenic mutations to drive frank prostate adenocarcinoma. To search for such ETS-cooperating oncogenic events, we focused on a well-studied prostate tumor suppressor  NKX3 . 1 , as loss of  NKX3 . 1  is another common genetic alteration in human prostate cancer. Previous studies have shown that deletions at 8p21 (harboring  NKX3 . 1 ) and 21q22 (resulting in  TMPRSS2-ERG  fusion) were both present in a subtype of prostate cancer cases, and that ERG can lead to epigenetic silencing of  NKX3 . 1  in prostate cancer cells, whereas NKX3.1 can in turn negatively regulate  TMPRSS2-ERG  fusion expression via suppression of the  TMPRSS2  promoter activity. We recently generated knockin mouse models for  TMPRSS2-ERG  and  TMPRSS2-ETV1  fusions, utilizing the endogenous  Tmprss2  promoter. We crossed these knockin models to an Nkx3.1 knockout mouse model. In  Tmprss2-ERG;Nkx3.1 +/-   (or   -/-  ) male mice, although we observed a slight but significant upregulation of  Tmprss2-ERG  fusion expression upon  Nkx3 . 1  loss, we did not detect any significant cooperation between these two genetic events to enhance prostate tumorigenesis  in vivo . Furthermore, retrospective analysis of a previously published human prostate cancer dataset revealed that within  ERG -overexpressing prostate cancer cases,  NKX3 . 1  loss or deletion did not predict biochemical relapse after radical prostatectomy. Collectively, these data suggest that although  TMPRSS2-ERG  fusion and loss of  NKX3 . 1  are among the most common mutational events found in prostate cancer, and although each of them can sensitize prostate epithelial cells for cooperating with other oncogenic events, these two events themselves do not appear to cooperate at a significant level  in vivo  to enhance prostate tumorigenesis.

Genetic Interaction between Tmprss2-ERG Gene Fusion and Nkx3.1-Loss Does Not Enhance Prostate Tumorigenesis in Mouse Models