Research Repository

Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression

Brooke, GN and Parker, MG and Bevan, CL (2008) 'Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression.' Oncogene, 27 (21). pp. 2941-2950. ISSN 0950-9232

Full text not available from this repository.


Prostate tumour growth depends on androgens; hence treatment includes androgen ablation and anti-androgens. Eventually tumours progress and in approximately 30% of patients this is associated with mutation of the androgen receptor. Several receptor variants associated with advanced disease show promiscuous activation by other hormones and anti-androgens. Such loss of specificity could promote receptor activation, hence tumour growth, in the absence of conventional ligands, explaining therapy failure. We aimed to elucidate mechanisms by which alternative ligands promote receptor activation. The three most commonly identified variants in tumours (with amino-acid substitutions H874Y, T877A and T877S) and wild-type receptor showed differences in co-activator recruitment dependent upon ligand and the interaction motif utilized. Co-expression and knockdown of co-activators that bind via leucine or phenylalanine motifs, combined with chromatin immunoprecipitation and quantitative PCR, revealed these preferences extend to co-activator recruitment in vivo and affect receptor activity at the transcriptional level, with subsequent effects on target gene regulation. The findings suggest that mutant receptors, activated by alternative ligands, drive growth via different mechanisms to androgen-activated wild-type receptor. Tumours may hence behave differently dependent upon any androgen receptor mutation present and what ligand is driving growth, as distinct subsets of genes may be regulated. © 2008 Nature Publishing Group All rights reserved.

Item Type: Article
Uncontrolled Keywords: androgen receptor; prostate cancer; co-activators; anti-androgens; SARMs
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 04 Dec 2013 12:30
Last Modified: 20 Jun 2022 12:55

Actions (login required)

View Item View Item