FUNCTIONAL-CHARACTERIZATION OF MUTANT ANDROGEN RECEPTORS FROM ANDROGEN-INDEPENDENT PROSTATE-CANCER

Mutations in the androgen receptor (AR), that alter steroid hormone sp ecificity have been identified in a series of androgen-independent pro state cancers, To address the functional properties of these mutant AR s that may have contributed to their selection in vivo, responses to a series of steroid hormones and antiandrogens were assessed, CV-1 cell s mere cotransfected with wild-type or mutant ARs and a luciferase rep orter plasmid regulated by an androgen-responsive element, Dose-respon se curves were analyzed for 5 alpha-dihydrotestosterone, the most acti ve androgen in normal prostate, and androstenedione, a major androgen derived from the adrenals, Although the mutant ARs responded to both o f these steroids, the responses were equivalent to or less than the wi ld-type AR, In contrast, responses to flutamide, a competitive antagon ist of the mild-type ARI were markedly increased by three of the mutat ions, Similar responses mere observed with a second antiandrogen, nilu tamide, Bicalutamide, another antiandrogen related to flutamide, remai ned an antagonist for these mutant ARs, Finally, flutamide was observe d to be a weak partial agonist of the wild-type AR in this system, The se results indicate that flutamide used in conjunction with androgen a blation therapy for prostate cancer may select for tumor cells with fl utamide-inducible ARs.