The Role of Androgen Receptor Modification in the Development of Drug-Resistant Breast Cancer
The most common targeted drug treatment option for pre-menopausal women with ER+ breast cancer (BCa) is Tamoxifen. Roughly 70% of women diagnosed with breast cancer are diagnosed with ER+ breast cancer, nearly half of which develop resistance rendering treatment ineffective and often leading to metastasis of the cancer and subsequent mortality. For patients who develop Tamoxifen resistance (TamR), other treatment options are limited to highly toxic non-targeted chemotherapy. Our long-term objective is to delineate targetable pathways that drive resistance to Tamoxifen in hormone positive BCa. Tamoxifen resistant ER+ BCa cells exhibit increased levels of global SUMO 2/3 conjugation; SUMO post-translational modification directs protein function and stability. The androgen receptor (AR) is a target for SUMO-modification in TamR BCa and SUMOylation of the AR supports hyper-activation of AR and metastatic nature of the TamR cells. While we know AR SUMOylation favors TamR cell proliferation, it is unknown if AR SUMOylation supports the development of resistance to the drug Tamoxifen. We predict that AR SUMOylation supports the development of resistance to the drug Tamoxifen. We are investigating, using western blots, when the SUMOylation of the AR occurs upon treatment of Tamoxifen-sensitive ER+ BCa cells. Additionally, mRNA quantification will be performed to assess SUMO-regulating enzymes. We are also investigating if treatment with combination of SUMO inhibitor and AR antagonists prevent resistance to tamoxifen and development of more drug resistant cancer spheroids.