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Cancer Discov. 2013 Nov;3(11):1245-53. doi: 10.1158/2159-8290.CD-13-0172. Epub 2013 Sep 11.

Androgen receptor signaling regulates DNA repair in prostate cancers.

Author information

1
1Human 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.

Abstract

We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining.

SIGNIFICANCE:

We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer.

PMID:
24027196
PMCID:
PMC3888815
DOI:
10.1158/2159-8290.CD-13-0172
[Indexed for MEDLINE]
Free PMC Article

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