Androgen signaling and prostate cancer
Prostate cancer (PCa) remains a key challenge for men’s health and a significant economic burden on society. Majority of primary prostate tumors are treated successfully by radical prostatectomy or external beam radiotherapy, but tumors can progress to invasive and disseminated disease. Patients with metastatic PCa are treated with androgen deprivation therapy; whereas the initial response is very high, complete remissions are rare and disease progression resumes after a median of 2-3 years. The emergent castration-resistant PCa (CRPC) may respond to recently developed AR inhibitory drugs, but this is also short-lived as resistance develops in a few months after which prognosis is very unfavorable.
The basis of androgen deprivation therapy is a large body of research implicating androgen signalling in all phases of PCa. The effects of androgens are mediated by the androgen receptor (AR), an androgen regulated transcription factor. AR signaling is critical to the development and function of the normal prostate, in the progression from primary to metastatic disease, as well as a hallmark of CRPC. The downstream pathways regulated by AR may also be important in the final stage of AR-independent disease. Therefore, discovering mechanisms of AR-driven gene regulation and their downstream effects in tumor cells is imperative. Despite extensive global analyses of AR target gene expression, their functional characterization and relevance in PCa is still limited at present.
We have previously identified components of AR signalling and its crosstalk with other signalling pathways, including potential biomarkers and therapeutic targets. In particular, our efforts focus on a few genes cloned in our laboratory, such as the six transmembrane protein of prostate 1 and 2 (STAMP1 and STAMP2, also known as STEAPs), and kallikrein related peptidase 4 (KLK4) that are AR regulated and/or highly restricted to prostate for expression. We have shown that all three are essential for PCa growth and survival, and that they impact a number of key cellular signaling pathways. We are currently characterizing these proteins functionally, their interacting partners, and how they steer PCa growth, as well as exploring methods to block their function for potential applications in the clinic.