Investigating the Oncogenic Role of NKX3.1 in Prostate Cancer

Prostate cancer is a unique disease in that it is fueled by androgen receptor (AR) signaling. In the clinic, AR signaling is disrupted by removing androgens via chemical castration and employing AR-antagonists such as enzalutamide. Unfortunately, these therapies are short-lived, resistance sets in, and tumors evolve to a form of the disease called castration-resistant prostate cancer (CRPC). At this stage, therapeutic options are virtually exhausted and palliative care is pursued. There is a growing need to characterize other molecular players that cooperate with AR or play a unique role in CRPC on their own. One such potential candidate is the homeobox transcription factor NKX3.1. Though NKX3.1 is traditionally thought of as a tumor suppressor, it has been reported to promote cancer cell survival by cooperating with AR. The role of NKX3.1 as a tumor suppressor contradicts its profile as a diagnostic biomarker for advanced prostate cancer. This knowledge has led me to hypothesize that prostate cancer cell survival is dependent on NKX3.1 expression during late-stage disease. I will test this hypothesis by determining if NKX3.1 is important for prostate cancer cell growth and survival by employing siRNA to transiently knockdown NKX3.1. I will also determine if NKX3.1 promotes resistance to AR-targeted therapy by stably overexpressing NKX3.1 and probing growth characteristics in the presence of enzalutamide. These experiments will reveal the oncogenic role of NKX3.1 in prostate cancer, ultimately paving the way for its potential as a therapeutic target in treating advanced prostate cancer.