Mutations of Receptor for Androgens

Androgens are the major hormones that stimulate the prostate to grow. Their action in the cell is mediated by a specific protein called a receptor. When androgens enter the prostatic cell, they bind to this receptor, like a key in a lock, and this steroid -receptor complex activates celluar growth and function. Thus, androgen receptors are very important for hormone action.

Dr. Evelyn Barrack has recently demonstrated that as prostate cancer progresses, the receptor for androgens may undergo mutations. Recently, Dr. Schoenberg and Dr. Barrack have demonstrated that a specific mutation in the receptor is associated with a paradoxical response to hormones. Flutamide is an antiandrogen that blocks the binding of androgens to the receptor. It is frequently used in combination with castration or treatment with an LHRH agonist. Some people believe that flutamide may be useful in providing total androgen ablation. However, in some patients flutamide actually stimulates cancer growth and PSA levels paradoxically fall when flutamide is discontinued. They demonstrated that in one patient who had this paradoxical stimulation by flutamide, there was a mutation in the androgen receptor. Further elucidation of androgen receptor mechanisms may make it possible to improve hormonal therapy for prostate cancer.

1. Schoenberg, M.P., Hakimi, J.M., Wang, S., Bova. G.S., Epstein, J.1., Fishbeck, K.H., Isaacs, W.B., Walsh, P.C. & Barrack, E.R.: Microsatellite mutation (CAG_24-18) in the androgen receptor gene in human prostate cancer. BBRC 198:74-80, 1994.