Open AccessTMPRSS2-ERG promotes the initiation of prostate cancer by suppressing oncogene-induced senescence
Author(s) -
Lei Fang,
Dongmei Li,
Juan Juan Yin,
Hong Pan,
Huihui Ye,
Joel Bowman,
Brian J. Capaldo,
Kathleen Kelly
Publication year - 2022
Publication title -
cancer gene therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.535
H-Index - 86
eISSN - 1476-5500
pISSN - 0929-1903
DOI - 10.1038/s41417-022-00454-5
Subject(s) - tmprss2 , cancer research , pten , carcinogenesis , biology , erg , oncogene , senescence , kras , prostate cancer , prostate , pi3k/akt/mtor pathway , cancer , gene , mutation , signal transduction , microbiology and biotechnology , cell cycle , genetics , medicine , retina , disease , covid-19 , neuroscience , infectious disease (medical specialty)
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.