Castration-resistant prostate cancer: Adaptive responses in the androgen axis

The androgen signaling axis in prostate cancer is associated with multiple adaptive mechanisms in response to castration. Herein we review these adaptations with an emphasis on recent molecular insights into the growth and development of castration resistant prostate cancer (CRPC). Alterations include both conventional and novel intracrine androgen synthesis pathways and androgen transport as well as androgen receptor (AR) overexpression, mutation, and splice variation. Each of these underlying mechanisms are potentially linked to post-castration growth, especially after treatment with newer hormonal agents such as abiraterone and enzalutamide. Post-translational AR modifications are well documented and these can affect receptor activity, stability, localization, and interaction with other proteins. Changes in recruitment of androgen receptor associated co-activators/repressors and a distinct AR-induced transcriptional program can dramatically alter proliferation, invasion, and metastasis in a ligand and context-dependent manner. Numerous previously uncharacterized non-coding RNAs, some of which are androgen regulated, may also have important biological function in this disease. Taken together, the view of CRPC has changed dramatically in the last several years. This has occurred not only within the setting of multiple treatment paradigm changes, but also as a multiplicity of potential molecular mechanisms underlying this disease state have been explored and discovered.