Effect of a short CAG (glutamine) repeat on human androgen receptor function

BACKGROUND The human androgen receptor ( AR ) gene contains an uninterrupted CAG repeat that is polymorphic in length in the general population (range, 11–31 CAG's; median, 21). The CAG repeat encodes a glutamine repeat in the N‐terminal transactivation domain of the AR protein. We previously reported that a 17‐CAG AR gene was much more common in a cohort of men with prostate cancer (8.5%) than in the general European American population (1.3%). This suggested that a 17‐CAG repeat may have pathophysiological consequences. The goal of the present study was to directly test the hypothesis that a 17‐CAG repeat might uniquely affect androgen action in human prostate cancer cells. METHODS DU145 cells, lacking endogenous AR, were transiently transfected with an AR expression plasmid (with a CAG repeat ranging in length from 14 to 25) and an androgen‐responsive reporter plasmid (PSA‐luciferase). RESULTS We found a significant effect of CAG repeat length on AR protein levels per unit amount of DNA transfected (one‐way ANOVA, P  = 0.02), indicating the need to express transactivation data per unit amount of AR protein. CAG17 AR had 40% more transactivation activity per unit amount of AR protein than CAG21 AR ( P  < 0.01). CONCLUSIONS Thus, an AR with a 17‐CAG repeat may mediate more efficacious growth stimulation of androgen‐dependent prostate epithelial cells, and thereby increase the risk that prostate cancer cells develop more efficiently into a clinically significant cancer. © 2003 Wiley‐Liss, Inc.