Functional characterization of mutant androgen receptors from androgen-independent prostate cancer.
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.
Fenton
M A
MA
Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Hospital Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Shuster
T D
TD
Fertig
A M
AM
Taplin
M E
ME
Kolvenbag
G
G
Bubley
G J
GJ
Balk
S P
SP
D019943:Amino Acid Substitution; D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology*; D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005485:Flutamide / Q000031:analogs & derivatives / Q000494:pharmacology; D017930:Genes, Reporter; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D008156:Luciferases / Q000235:genetics; D008297:Male; D017354:Point Mutation; D011374:Progesterone / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection; D001616:beta-Galactosidase / Q000235:genetics
D000726:Androgen Antagonists; D000728:Androgens; D007093:Imidazoles; D048289:Imidazolidines; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D013196:Dihydrotestosterone; C014290:hydroxyflutamide; D000735:Androstenedione; D011374:Progesterone; D004958:Estradiol; C021277:nilutamide; D005485:Flutamide; D008156:Luciferases; D001616:beta-Galactosidase