TMPRSS2-ERG promotes the initiation of prostate cancer by suppressing oncogene-induced senescence

ERG translocations are commonly involved in the initiation of prostate neoplasia, yet previous experimental approaches have not addressed mechanisms of oncogenic inception. Here, in a genetically engineered mouse model, combining TMPRSS2-driven ERG with Kras(G12D) led to invasive prostate adenocarcinomas, while ERG or Kras(G12D) alone were non-oncogenic. In primary prostate luminal epithelial cells, following inducible oncogenic Kras expression or Pten depletion, TMPRSS2-ERG suppressed oncogene-induced senescence, independent of TP53 induction and RB1 inhibition. Oncogenic KRAS and TMPRSS2-ERG synergized to promote tumorigenesis and metastasis of primary luminal cells. The presence of TMPRSS2-ERG compared to a wild-type background was associated with a stemness phenotype and with relatively increased RAS-induced differential gene expression for MYC and mTOR-regulated pathways, including protein translation and lipogenesis. In addition, mTOR inhibitors abrogated ERG-dependent senescence resistance. These studies reveal a previously unappreciated function whereby ERG expression primes preneoplastic cells for the accumulation of additional gene mutations by suppression of oncogene-induced senescence.

Automated summary

ERG translocations play a key role in the initiation of prostate neoplasia. However, the mechanisms of oncogenic inception have not been fully understood. In this study, a genetically engineered mouse model was used to investigate the effects of combined TMPRSS2-driven ERG and Kras(G12D) on prostate adenocarcinomas. It was found that the presence of TMPRSS2-ERG, along with Kras(G12D), promoted tumorigenesis and metastasis of primary luminal cells. Additionally, TMPRSS2-ERG suppressed oncogene-induced senescence, leading to the accumulation of additional gene mutations. This study reveals a previously unknown function of ERG expression in priming preneoplastic cells for oncogenic mutations.