The androgen receptor: structure, mutations, and antiandrogens

Abstract

Androgens play a critical role not only in the physiological development of the prostate but also in the genesis of prostate cancer. The effects of androgen on the prostate gland and on the other tissues of the body are mediated by activation of the androgen receptor. The androgen receptor is a member of the superfamily of hormone receptors with a DNA-binding site, two zinc finger domains, and a hormone-binding site. Mutations in this receptor can be associated with loss of function or chronic endogeneous activation, depending upon the site of change. Androgens effect a conformal change in the structure of the androgen receptor associated with a change in protein phosphorylation. The androgen receptor can be activated by additional ligands affecting the hormone-binding site besides androgens. Activators and repressors of the androgen receptor modify this protein's function and are very delicately balanced such that disruptions of either function are associated with a disease state. Antiandrogens, which bind to the receptor and thus down-regulate the effects of endogeneous circulating androgens, remain the first line treatment for palliation of advanced prostate cancer. Mutations in the receptor are associated with a change in function of such compounds from antagonist to agonist in vitro. Newer evidence suggests there may be a role of intermittent androgen suppression rather than continuous suppression, perhaps by preventing overgrowth of hormone independent tumor cells. Future research focuses on the development of drugs directed at suppressing the androgen drive of the androgen sensitive clone of the tumor and making the nonsensitive subset more susceptible to cytotoxics.