Elucidating the role of androgen receptor (AR) in mediating radioresistance in AR-positive breast cancer How to make treatment more effective for the women with aggressive breast cancers for whom standard therapies are ineffective; rationally designed treatment intensification Radiation therapy (RT) remains a mainstay of current clinical management of breast cancer but is least effective in women with triple-negative breast cancer (TNBC). Additionally, TNBC is the most lethal form of breast cancer, but the molecular drivers of this radioresistance are currently unknown. Given the fundamental lack of knowledge regarding the mediators of radiation resistance and a furthered lack of targeted agents for TNBC, it is clear that the development of additional targets for radiosensitization represents a critical unmet clinical need. We previously identified that the androgen receptor (AR) plays an important role in mediating radioresistance in AR-positive TNBC, though the exact mechanism of this radioresistance remains unclear. Although antiandrogen therapy is effective in radiosensitizing AR+ TNBC, it is unclear whether antiandrogen treatment in AR+ estrogen receptor-positive (ER+) breast cancer is similarly effective. As up to 70% of ER+ tumors also express AR, effective targeting of AR for radiosensitization has the potential to improve local control in all AR+ breast cancer, not just AR+ TNBC. The goal of the proposed research is to develop more effective radiosensitizing treatment strategies for woman with aggressive forms of breast cancer-including AR+ TNBC and AR+ Luminal B cancers that are ER+. We hypothesize that AR mediates radioresistance in all AR+ breast cancer, and not just AR+ TNBC. We further hypothesize that AR expression confers this radioresistance by controlling AR-mediated transcription and activation of DNA repair genes after ionizing radiation and that this radioresistance can be reversed by inhibition of AR-signaling using second generation anti-androgens. To test these hypotheses, we will determine the degree of radiosensitization using enzalutamide with RT in AR+/ER+ patient derived xenograft (PDX) cell lines and PDX models. We will also determine the gene transcription changes that occur with anti-androgen treatment after radiation to determine how DNA binding of AR and AR-mediated transcription changes after radiation treatment and inhibition of AR with antiandrogens with RT treatment.