ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer

The mechanisms underlying ETS-driven prostate cancer initiation and
progression remain poorly understood due to a lack of model systems that
recapitulate this phenotype. We generated a genetically engineered mouse
with prostate-specific expression of the ETS factor, ETV4, at lower and
higher protein dosages through mutation of its degron. Lower-level
expression of ETV4 caused mild luminal cell expansion without histologic
abnormalities and higher-level expression of stabilized ETV4 caused
prostatic intraepithelial neoplasia (mPIN) with 100% penetrance within 1
week. Tumor progression was limited by p53-mediated senescence and Trp53
deletion cooperated with stabilized ETV4. The neoplastic cells expressed
differentiation markers such as Nkx3.1 recapitulating luminal gene
expression features of untreated human prostate cancer. Single-cell and
bulk RNA-sequencing showed stabilized ETV4 induced a novel luminal-derived
expression cluster with signatures of the cell cycle, senescence, and
epithelial to mesenchymal transition. These data suggest that ETS
overexpression alone, at sufficient dosage, can initiate prostate
neoplasia.