Functional characterization of mutant androgen receptors from androgen-independent prostate cancer.

TLDR

Mutations that alter steroid hormone specificity in the androgen receptor have been identified in androgen‑independent prostate cancers. The study assessed how these mutant ARs respond to various steroid hormones and antiandrogens to understand their potential role in tumor selection. The authors transfected CV‑1 cells with wild‑type or mutant ARs and a luciferase reporter, then generated dose‑response curves for 5α‑dihydrotestosterone, androstenedione, and antiandrogens. Mutant ARs responded to natural steroids as well or less than wild type, but showed markedly increased activation by flutamide and nilutamide while remaining antagonized by bicalutamide; flutamide also acted as a weak partial agonist of the wild type, indicating that flutamide combined with androgen ablation could select for flutamide‑inducible ARs.

Abstract

Mutations in the androgen receptor (AR), that alter steroid hormone specificity have been identified in a series of androgen-independent prostate cancers. To address the functional properties of these mutant ARs that may have contributed to their selection in vivo, responses to a series of steroid hormones and antiandrogens were assessed. CV-1 cells were cotransfected with wild-type or mutant ARs and a luciferase reporter plasmid regulated by an androgen-responsive element. Dose-response curves were analyzed for 5alpha-dihydrotestosterone, the most active androgen in normal prostate, and androstenedione, a major androgen derived from the adrenals. Although the mutant ARs responded to both of these steroids, the responses were equivalent to or less than the wild-type AR. In contrast, responses to flutamide, a competitive antagonist of the wild-type AR, were markedly increased by three of the mutations. Similar responses were observed with a second antiandrogen, nilutamide. Bicalutamide, another antiandrogen related to flutamide, remained an antagonist for these mutant ARs. Finally, flutamide was observed to be a weak partial agonist of the wild-type AR in this system. These results indicate that flutamide used in conjunction with androgen ablation therapy for prostate cancer may select for tumor cells with flutamide-inducible ARs.