Alterations in DNA repair promote tumor development, but the impact on tumor progression is poorly understood. Here, discovery of a biochemical circuit linking hormone signaling to DNA repair and therapeutic resistance is reported. Findings demonstrate that androgen receptor (AR) activity is induced by DNA damage, and promotes expression and activation of a gene expression program governing DNA repair. Subsequent investigation revealed that activated AR promotes resolution of double-strand breaks and resistance to DNA damage both in vitro and in vivo. Mechanistically, DNAPKcs was identified as a key target of AR after damage, controlling AR-mediated DNA repair and cell survival after genotoxic insult. Finally, DNAPKcs was shown to potentiate AR function, consistent with a dual role in both DNA repair and transcriptional regulation. Combined, these studies identify the AR-DNAPKcs circuit as a major effector of DNA repair and therapeutic resistance, and establish a new node for therapeutic intervention in advanced disease.

Therapies that target the synthesis of estrogen or the function of estrogen receptor(s) have been developed to treat breast cancer. While these approaches have proven to be beneficial to a large number of patients, both de novo and acquired resistance to these drugs is a significant problem. Recent advances in our understanding of the molecular mechanisms that contribute to resistance have provided a means to begin to predict patient responses to these drugs and develop rational approaches for combining therapeutic agents to circumvent or desensitize the resistant phenotype. Here, we review common mechanisms of antiestrogen resistance and discuss the implications for prediction of response and design of effective combinatorial treatments.