Molecular determinants of resistance to antiandrogen therapy.
Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.
Chen
Charlie D
CD
Department of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
Welsbie
Derek S
DS
Tran
Chris
C
Baek
Sung Hee
SH
Chen
Randy
R
Vessella
Robert
R
Rosenfeld
Michael G
MG
Sawyers
Charles L
CL
D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D001483:Base Sequence; D017931:DNA Primers; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011944:Receptors, Androgen / Q000502:physiology
D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D017931:DNA Primers; D011944:Receptors, Androgen