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Androgen receptor signaling regulates DNA repair in prostate cancers

William R Polkinghorn1, Joel S Parker, Man X Lee

  • 11Human Oncology Pathogenesis Program, 2Developmental Biology Program, and 3Immunology Program; Departments of 4Radiation Oncology, 5Medicine, 6Surgery, and 7Pathology; 8Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center; 9Department of Genetics, Albert Einstein College of Medicine, New York, New York; 10Department of Genetics; and 11Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.

Cancer Discovery
|September 13, 2013
PubMed
Abstract

Insights

Androgen receptor (AR) controls DNA repair genes, impacting prostate cancer radioresistance. Androgen deprivation therapy may enhance radiotherapy by downregulating these AR-regulated DNA repair genes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Prostate cancer treatment often involves androgen deprivation therapy (ADT) and radiotherapy.
  • The role of the androgen receptor (AR) in regulating DNA repair and its impact on treatment resistance is not fully understood.

Purpose of the Study:

  • To investigate the role of the AR in regulating DNA repair genes in prostate cancer.
  • To elucidate the mechanism by which ADT might synergize with ionizing radiation.

Main Methods:

  • Utilized a castration-resistant prostate cancer model.
  • Employed RNA-sequencing (RNA-seq) and ChIP-sequencing (ChIP-seq).
  • Assessed DNA repair capacity, DNA damage, and clonogenic survival following various treatments.

Main Results:

  • AR regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance.
  • Second-generation antiandrogen therapy downregulated DNA repair genes in a castration-resistant prostate cancer model.
  • Prostate cancers exhibit AR transcriptional output correlating with DNA repair gene expression.
  • Antiandrogen treatment led to increased DNA damage and decreased clonogenic survival.
  • Antiandrogen treatment resulted in decreased classical nonhomologous end-joining.

Conclusions:

  • The AR regulates a network of DNA repair genes.
  • This provides a potential mechanism for the synergy between androgen deprivation and radiotherapy in prostate cancer treatment.

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