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TMPRSS2-ERG Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in PTEN and TP53-Mutated Prostate Cancer

Alexandra M Blee1,2, Yundong He1, Yinhui Yang1,3

  • 1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 31, 2018
PubMed

Insights

The oncogenic transcription factor ERG restricts prostate cancer lineage plasticity and maintains antiandrogen sensitivity in PTEN/TP53-altered tumors. ERG fusion may serve as a biomarker for guiding treatment in RB1-intact prostate cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Prostate cancer therapy resistance is linked to lineage plasticity, driven by alterations in tumor suppressor genes PTEN and TP53.
  • ERG oncogenic transcription factor overexpression occurs in ~50% of prostate cancers, often co-occurring with PTEN/TP53 alterations.
  • The specific role of ERG in the lineage plasticity of PTEN/TP53-altered prostate cancer remains unclear.

Purpose of the Study:

  • To investigate the role of ERG in lineage plasticity within PTEN/TP53-altered prostate cancer.
  • To understand the combined impact of PTEN, TP53, and ERG alterations on prostate cancer progression and therapy resistance.
  • To identify ERG-dependent therapeutic vulnerabilities in PTEN/TP53-altered prostate cancer.

Main Methods:

  • Generation of a Pten-negative/Trp53-mutated/ERG-overexpressing mouse model for prostate cancer.
  • Integration of RNA-sequencing and ERG chromatin immunoprecipitation-sequencing (ChIP-seq) to identify ERG-regulated pathways.
  • Evaluation of ERG-dependent sensitivity to enzalutamide and palbociclib in cell lines, xenografts, and patient cohorts.

Main Results:

  • Transgenic ERG expression in mice prevented AR expression decrease and luminal gene loss induced by Pten/Trp53 alterations.
  • ERG suppressed cell cycle genes, leading to RB hypophosphorylation and repressed E2F1 activity, restricting lineage plasticity.
  • ERG restricted adenocarcinoma plasticity and maintained antiandrogen sensitivity; CDK4/6 inhibition delayed tumor growth in ERG-negative tumors.

Conclusions:

  • ERG has a novel function in restricting lineage plasticity and maintaining antiandrogen sensitivity in PTEN/TP53-altered prostate cancer.
  • ERG fusion can serve as a predictive biomarker for guiding treatment decisions in PTEN/TP53-altered, RB1-intact prostate cancer.
  • Targeting CDK4/6 may benefit ERG-negative prostate tumors.

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