The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology
The steroid nuclear receptor superfamily encodes proteins that selectively bind lipid and cholesterol derived ligands. Vertebrate steroid nuclear receptors include the estrogen receptor alpha (ERα), androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), and mineralocorticoid receptor (MR) (1). Steroid receptor ligands are highly lipophilic in nature and as a consequence bind to a hydrophobic cavity in the α-helical fold (2), this in turn, controls coregulatory interactions by inducing allosteric changes on the receptor surface. Many studies in hormone driven cancers focus on the expression of nuclear receptors however, arguably it is the level of steroid and relative affinity for the receptor present that is more pertinent as they are the vital stimulus required for receptor activation and cellular responses (3). Many breast cancer studies have shown that serum estrogens and androgens are associated with both increased and decreased breast cancer risk (4–6). Although much research in breast cancer has focused on ERα and its steroid ligands it has been shown that in subsets of ER and PR negative primary breast carcinomas, molecular profiles indicate hormonally regulated transcription still occurs (7). This suggests the involvement of other sex steroids and/or their receptors such as the most abundantly expressed nuclear receptor in breast cancer, AR. Renewed focus on AR in breast cancer has shown that alterations in the antagonist relationship between ERα and AR may play a role in the development of breast cancer, and in particular, skewed AR ERα expression ratio may be a factor that influences the development of resistance to ERα -directed therapy (8–10). Here, we describe recent findings on AR in breast cancer with a renewed interest in elucidating the role of sex steroids and their metabolites in disease progression.