Targeting steroid hormone receptor pathways in the treatment of hormone dependent cancers

Sex steroid hormones play a central role in the development and progression of prostate and breast cancers. The biological functions of these and other steroid hormones are mediated by a family of closely related steroid hormone receptors (SHRs), with the androgen receptor (AR) mediating the effects of testosterone and related androgens, and the classical estrogen receptor (ERalpha) mediating the effects of estradiol. Recent studies have begun to elucidate the complex pathways through which SHRs regulate gene expression, and their interaction with other cellular pathways. These studies have also begun to reveal molecular mechanisms underlying the diverse spectrum of effects mediated by steroid hormone analogues in different tissues. A major advance has been the finding that certain drugs induce unique conformational changes in SHRs that alter their interactions with transcriptional coactivator and corepressor proteins, resulting in cell type specific responses. These unique conformational changes appear responsible for the tissue specific effects of the selective estrogen receptor modulators (SERMs) in breast cancer. SHRs are clearly well established therapeutic targets in cancer, and drug development has continued to focus on agents that either block steroid hormone production or bind to and modulate their receptors. The identification of multiple proteins and pathways that mediate the downstream functions of SHRs may eventually provide additional therapeutic targets. This review outlines the basic biology of SHR structure and function, with a focus on AR and ERalpha. Hormonal therapies in prostate and breast cancer that directly target AR and ERalpha, respectively, are then presented and possible novel drug targets in the SHR pathway are discussed.