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. Cancer Discov; 3(11); 1245–53. ©2013 AACR. See related commentary by Bartek et al., p. 1222 This article is highlighted in the In This Issue feature, p. 1207

Population-based estimates demonstrate that black men are more likely to be diagnosed with prostate cancer, more likely to present with distant metastases, and nearly 2.5 times more likely die of the disease when compared with non-Hispanic white men.¹ Black men are also more likely to have comorbid illness such as cardiovascular disease² and diabetes,³ diagnoses that are negatively associated with survival outcomes with or without prostate cancer. These disparities are a major health concern and an area of ongoing research and national funding.⁴ Each year, the Surveillance, Epidemiology, and End Results (SEER) database reports age-adjusted prostate cancer–specific mortality (PCSM) rates. However, fully adjusting for measurable and unmeasurable confounders within these registries is difficult.^5-7 Black men with prostate cancer have lower socioeconomic status,⁸ are diagnosed at a later stage,⁹ and receive less guideline-concordant care.^10,11