Androgen regulation of the cell cycle in prostate cancer

Androgens control both growth and differentiation of the normal prostate gland and are the major factors on which prostate cancer cells depend for growth and survival. However, the mechanisms by which androgens act upon the cell cycle machinery to regulate both growth and differentiation are not fully understood. Research over the past decades reveals that expression of several key cell cycle regulators such as SKP2, p27^KIP1, E2F1, and EZH2 is regulated by androgens in a biphasic manner, that is, stimulated by low dose of androgens but repressed by higher doses of androgens. Because age is one of the key risk factors for prostate cancer, it is possible that with the decline in the levels of serum testosterone during aging, androgenic regulation of cell cycle genes may shift from the pro-differentiation to pro-proliferative mode. It is also likely that residual levels of androgens produced via intracrine mechanism in castration-resistant prostate cancer may be sufficient to activate androgen-mediated pro-proliferative gene program, but insufficient to initiate anti-proliferative program, thereby favoring castration-resistant progression. Finally, the possibility that the androgen-regulated anti-proliferative gene program may be outlawed by frequently deregulated oncogenic pathways in human prostate cancers is discussed.