ETS Factors Reprogram the Androgen Receptor Cistrome and Prime Prostate Tumorigenesis in Response to PTEN Loss

Nat Med. 2013 Aug;19(8):1023-9. doi: 10.1038/nm.3216. Epub 2013 Jun 30.

Abstract

Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN-deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / pathology*
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Genes / genetics*
  • Histones / metabolism
  • Humans
  • Lysine / metabolism
  • Male
  • Mice
  • Oncogene Proteins / metabolism
  • PTEN Phosphohydrolase / deficiency*
  • PTEN Phosphohydrolase / metabolism
  • Phenotype
  • Principal Component Analysis
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*
  • Proto-Oncogene Proteins c-ets / metabolism*
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism*
  • Signal Transduction / genetics
  • Transcription Factors / metabolism
  • Transcriptional Regulator ERG
  • Transcriptome / genetics

Substances

  • DNA-Binding Proteins
  • ERG protein, mouse
  • ETV1 protein, human
  • Histones
  • Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • Receptors, Androgen
  • Transcription Factors
  • Transcriptional Regulator ERG
  • PTEN Phosphohydrolase
  • Lysine

Associated data

  • GEO/GSE46329
  • GEO/GSE46360
  • GEO/GSE46799
  • GEO/GSE47119
  • GEO/GSE47120