title: Molecular determinants of resistance to antiandrogen therapy.
abstract: 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.
authors.affiliation: Department of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Charlie D
authors.initials: CD
authors.lastname: Chen
authors.forename: Derek S
authors.initials: DS
authors.lastname: Welsbie
authors.forename: Chris
authors.initials: C
authors.lastname: Tran
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Baek
authors.forename: Randy
authors.initials: R
authors.lastname: Chen
authors.forename: Robert
authors.initials: R
authors.lastname: Vessella
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: 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
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D017931:DNA Primers; D011944:Receptors, Androgen