Abstract 1071: Impact of AR activation status on the DNA damage response.

Abstract Recent evidence implicates the androgen receptor (AR) as a critical modulator of the DNA damage response in prostate cancer. Treatment for locally advanced disease depends on combined radiation therapy and ablation of AR function, and clinical evidence strongly supports the contention that active AR reduces the response to radiotherapy. Moreover, it was reported in vitro that AR activation can induce DNA damage at sites of active transcription, thus providing additional evidence for crosstalk between the DNA damage response and AR pathways. Despite these observations, the underpinning mechanism by which AR alters the response to DNA damage remains unknown. Several lines of evidence will be discussed which illuminate a role for AR in the response to DNA damage. First, investigation in a battery of hormone-therapy sensitive prostate cancer cells (in which AR activity remains dependent on ligand binding) and in castrate resistant tumor cells (reflecting advanced disease wherein AR activity is enhanced) showed that androgen depletion enhances the response to ionizing radiation. Restoration of dihydrotestosterone reduced the response to radiation, thus demonstrating that ligand-induced AR activity promotes a resistance to radiation. Second, the mechanism by which AR promotes radioresistance was addressed. Preliminary findings indicate that in the presence of DNA damage, AR dramatically alters the rate of DNA damage repair independent of significant effects on cell cycle. Moreover, these studies uncovered an unexpected role for androgen-activated AR to alter expression and subsequent activity of genes critical for the DNA damage response, possibly through differential recruitment of AR to loci of key players in the response to damage. Finally, a series radioresistant prostate cancer model systems were developed, wherein the impact of AR on acquired radioresistance is under investigation; early studies in these models indicate that altered AR output is associated with acquired radioresistance. Combined, the studies to be presented reveal novel functions of androgen and AR in controlling the molecular and cellular response to DNA damage, and provide the basis for future studies directed at targeting DNA-damage specific AR activity in the course of human disease. Citation Format: Jonathan F. Goodwin, Matthew J. Schiewer, Felix Y. Feng, Karen E. Knudsen. Impact of AR activation status on the DNA damage response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1071. doi:10.1158/1538-7445.AM2013-1071