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.