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

Cancer Gene Ther. 2022 Oct;29(10):1463-1476. doi: 10.1038/s41417-022-00454-5. Epub 2022 Apr 7.


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 KrasG12D led to invasive prostate adenocarcinomas, while ERG or KrasG12D 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.

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Oncogene Proteins, Fusion / genetics
  • Oncogenes
  • Prostatic Neoplasms* / metabolism
  • Proto-Oncogene Proteins p21(ras)* / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transcriptional Regulator ERG / genetics
  • Transcriptional Regulator ERG / metabolism


  • ERG protein, human
  • Oncogene Proteins, Fusion
  • TMPRSS2-ERG fusion protein, human
  • Transcriptional Regulator ERG
  • TOR Serine-Threonine Kinases
  • Serine Endopeptidases
  • TMPRSS2 protein, human
  • Proto-Oncogene Proteins p21(ras)