Androgen Receptor Signaling: A Central and Evolving Theme in Prostate Cancer Treatment

The biological function of the male hormones (androgens) is orchestrated through the activation of the androgen receptor-mediated signaling events that are central to the development and maintenance of primary male sexual and secondary male characteristics. The androgen receptor belongs to the superfamily of nuclear receptors and functions as a transcription factor. The role of androgen signaling is well established in normal growth and development of the prostate gland. The androgen signaling dysfunctions due to alterations of androgen receptor and signaling molecules both upstream and downstream of androgen receptor are critical to prostate cancer progression after androgen deprivation therapy (ADT). Therapeutic targeting of various components of this biochemical pathway has remained the mainstay in the management of the advanced disease. Unfortunately, resistance to androgen signaling targeted drugs is inevitable. To overcome these challenges, new therapeutic strategies have continued to evolve including next generation of androgen receptor and androgen biosynthesis inhibitors, as well as chemotherapy agents and cancer driver mutation-targeted therapies. This review focuses on alterations of the key components of androgen signaling, especially the androgen receptor and the current state-of-the-art therapeutic strategies targeting this pathway in the management of advanced prostate cancer.