Mechanisms Underlying the Development of Androgen-Independent Prostate Cancer

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Abstract
Androgens are primary regulators of normal prostate as well as prostate cancer cell growth and proliferation. During androgen-dependent progression, prostate cancer cells depend on the androgen receptor as the primary mediator of growth and survival (10–12). When testosterone enters the cell, it is converted by the enzyme 5α-reductase to its active metabolite, dihydrotestosterone, a more active hormone with a 5- to 10-fold higher affinity for the androgen receptor. Dihydrotestosterone binds androgen receptors in the cytoplasm, causing phosphorylation, dimerization, and subsequent translocation into the nucleus, thereby binding to the androgen-response elements within the DNA, with consequent activation of genes involved in cell growth and survival (10). During androgen-independent progression, prostate cancer cells develop a variety of cellular pathways to survive and flourish in an androgen-depleted environment. Postulated and documented mechanisms include androgen receptor (AR) gene amplification, AR gene mutations, involvement of coregulators, ligand-independent activation of the androgen receptor, and the involvement of tumor stem cells (Fig. 1 ; refs. 8, 10–14).