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.