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ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss

Yu Chen1, Ping Chi, Shira Rockowitz

  • 1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. cheny1@mskcc.org

Nature Medicine
|July 3, 2013
PubMed

Insights

A new mouse model reveals how ETS factors like ERG drive prostate cancer by altering androgen receptor (AR) binding, especially when PTEN is lost. This discovery aids understanding of prostate oncogenesis and potential therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Prostate cancer development is complex, with ETS gene fusions and PTEN loss being key drivers.
  • Existing experimental models have limitations in studying ETS-mediated prostate oncogenesis.
  • Understanding the interplay between ETS factors and the androgen receptor (AR) pathway is crucial.

Purpose of the Study:

  • To develop and characterize a novel conditional mouse model for studying ERG-driven prostate cancer.
  • To investigate the functional consequences of ERG expression in the context of PTEN loss.
  • To explore the relationship between ETS factors, AR signaling, and PTEN status in both mouse models and human prostate cancer.

Main Methods:

  • Generation of a conditional mouse model with homogenous ERG expression in the prostate.
  • Induction of prostate cancer by combining ERG expression with homozygous Pten loss.
  • Chromatin immunoprecipitation sequencing (ChIP-seq) to assess AR binding.
  • RNA sequencing to analyze transcriptional changes.
  • Analysis of human prostate cancer cohorts to correlate ERG/ETV1 expression with AR output in PTEN-deficient tumors.

Main Results:

  • The novel mouse model exhibited accelerated, highly penetrant invasive prostate cancer upon Pten loss.
  • ERG significantly increased AR binding and restored AR transcriptional output in Pten-deficient prostates.
  • ERG-mediated transcriptional changes included upregulation of genes involved in cell death, migration, inflammation, and angiogenesis.
  • ETV1 similarly regulated the AR cistrome and transcription in human prostate cancer cells.
  • Clinical data showed ERG and ETV1 expression correlates with higher AR output in PTEN-deficient human prostate cancer.

Conclusions:

  • ETS factors, such as ERG and ETV1, play a critical role in prostate oncogenesis by reprogramming the AR cistrome.
  • The combination of ETS factor activity and PTEN loss creates a permissive environment for prostate cancer development and progression.
  • This study provides a valuable model for investigating ETS-mediated prostate cancer and highlights the altered AR signaling as a key mechanism.

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