ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer. Academic Article uri icon

Overview

abstract

  • 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 dosage 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 that stabilized ETV4 induced a previously unidentified luminal-derived expression cluster with signatures of cell cycle, senescence, and epithelial-to-mesenchymal transition. These data suggest that ETS overexpression alone, at sufficient dosage, can initiate prostate neoplasia.

publication date

  • April 5, 2023

Research

keywords

  • Prostatic Intraepithelial Neoplasia
  • Prostatic Neoplasms

Identity

PubMed Central ID

  • PMC10075989

Scopus Document Identifier

  • 85151804574

Digital Object Identifier (DOI)

  • 10.1126/sciadv.adc9446

PubMed ID

  • 37018402

Additional Document Info

volume

  • 9

issue

  • 14