MUTANT ANDROGEN RECEPTORS IN PROSTATIC TUMORS DISTINGUISH BETWEEN AMINO-ACID-SEQUENCE REQUIREMENTS FOR TRANSACTIVATION AND LIGAND-BINDING

Mutant androgen receptors are thought to contribute to hormone resista nce in prostate carcinoma. The part they play in this process, however , is ill-defined. Here we report on transactivation by 2 mutant androg en receptors from prostatic tumors with single amino-acid exchanges in their hormone-binding domains. These exchanges enhance the transactiv ation property of the receptors, particularly to androsterone and andr ostanediol, 2 metabolized derivatives of testosterone present in the p rostate. Additionally, they enhance the transactivation potential of t he mutant receptors to hydroxyflutamide an anti-androgen frequently us ed in hormone ablation therapy. The increased transactivation by the m utant receptors did not result from altered affinity of the receptors to the inducing ligands nor from measurable changes in conformation of the liganded receptors. Thus the single amino-acid exchanges identify differences in amino-acid-sequence requirements for transactivation a nd ligand binding in the hormone-binding domain of the androgen recept or. These results provide new insights into ligand-dependent transacti vation,and form a framework for the search for effective antagonists t o be use din prostate-cancer therapy. (C) 1995 Wiley-Liss, Inc.