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

Dan Li1, Yu Zhan1, Naitao Wang1

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Science Advances
|April 5, 2023
PubMed

Insights

Overexpression of the ETS factor ETV4 in mice initiates prostate cancer. This study reveals how ETV4 drives tumor development, offering new insights into ETS-driven prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Prostate cancer mechanisms driven by ETS factors are not well understood.
  • Lack of suitable model systems hinders research into ETS-driven prostate cancer.

Purpose of the Study:

  • To develop a mouse model for studying ETS-driven prostate cancer.
  • To investigate the role of ETV4 dosage in prostate cancer initiation and progression.

Main Methods:

  • Generated genetically engineered mice with prostate-specific ETV4 expression.
  • Utilized degron mutation to control ETV4 protein levels.
  • Performed histological analysis, RNA sequencing, and senescence assays.

Main Results:

  • High-level ETV4 expression induced prostatic intraepithelial neoplasia (mPIN) with 100% penetrance.
  • ETV4 overexpression initiated neoplasia by altering cell cycle, senescence, and epithelial-to-mesenchymal transition pathways.
  • Tumor progression was influenced by p53-mediated senescence and Trp53 deletion.

Conclusions:

  • Sufficient dosage of ETS factor overexpression alone can initiate prostate neoplasia.
  • ETV4 is a key driver in initiating ETS-driven prostate cancer.
  • The developed mouse model effectively recapitulates key features of human prostate cancer.

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