The role of the
androgen receptor (AR) signaling axis in the progression of
prostate cancer is a cornerstone to our understanding of the molecular mechanisms causing
castration-resistant
prostate cancer (CRPC). Resistance of advanced
prostate cancer to available treatment options makes it a clinical challenge that results in approximately 30,000 deaths of American men every year. Since the historic discovery by Dr. Huggins more than 70 years ago,
androgen deprivation
therapy (ADT) has been the principal treatment for advanced
prostate cancer. Initially, ADT induces apoptosis of
androgen-dependent
prostate cancer epithelial cells and regression of
androgen-dependent
tumors. However, the majority of patients with advanced
prostate cancer progress and become refractory to ADT due to emergence of
androgen-independent
prostate cancer cells driven by aberrant AR activation. Microtubule-targeting agents such as
taxanes,
docetaxel and
paclitaxel, have enjoyed success in the treatment of metastatic
prostate cancer; although new, recently designed mitosis-specific agents, such as the polo-
kinase and
kinesin-inhibitors, have yielded clinically disappointing results.
Docetaxel, as a first-line
chemotherapy, improves
prostate cancer patient survival by months, but
tumor resistance to these therapeutic agents inevitably develops. On a molecular level, progression to CRPC is characterized by aberrant AR expression, de novo intraprostatic
androgen production, and cross talk with other oncogenic pathways. Emerging evidence suggests that reactivation of epithelial-mesenchymal-transition (EMT) processes may facilitate the development of not only
prostate cancer but also
prostate cancer metastases. EMT is characterized by gain of mesenchymal characteristics and invasiveness accompanied by loss of cell polarity, with an increasing number of studies focusing on the direct involvement of
androgen-AR signaling axis in EMT,
tumor progression, and therapeutic resistance. In this article, we discuss the current knowledge of mechanisms via which the AR signaling drives therapeutic resistance in
prostate cancer metastatic progression and the novel therapeutic interventions targeting AR in CRPC.