Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance Academic Article uri icon


MeSH Major

  • Adenocarcinoma
  • Androgen Antagonists
  • Drug Resistance, Neoplasm
  • Prostatic Neoplasms
  • Retinoblastoma-Like Protein p107
  • Tumor Suppressor Protein p53


  • Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations that enable prostate cancer progression; identify mouse models for studying prostate cancer lineage plasticity; and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.

publication date

  • January 6, 2017



  • Academic Article



  • eng

PubMed Central ID

  • PMC5367887

Digital Object Identifier (DOI)

  • 10.1126/science.aah4199

PubMed ID

  • 28059767

Additional Document Info

start page

  • 78

end page

  • 83


  • 355


  • 6320