Endocrine mechanisms, androgen receptor and carcinogenesis, and hormone escape

Androgens play important roles during the development and maintenance of normal prostate as well as during the progression of prostate cancer. Testosterone, which is synthesized in the testes under the control of hormones from the pituitary and hypothalamus, is the primary androgen in men. Testosterone enters the prostate through blood stream and binds its cognate receptor (the androgen receptor or AR) in the acinar epithelial cells and the stromal cells. Like other nuclear hormone receptors, AR is a transcription factor, which is activated upon ligand binding in the cell cytoplasm. Activated AR enters the nucleus and regulates the transcription of genes involved in cell proliferation, survival, and differentiation. In this chapter, the endocrine mechanisms involve in the biosynthesis of androgen are discussed. Structural details of the androgen receptor, its changes in conformation upon ligand binding, various posttranslational modifications, and its coregulators are described. Specific roles of androgen/AR axis during the progression of prostate cancer and mechanisms by which AR activity is restored in prostate cancer cells of patients treated with androgen ablation therapy are discussed.