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. DOI https://doi.org/10.1038/sj.onc.1210955
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. DOI https://doi.org/10.1038/sj.onc.1210955
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. DOI https://doi.org/10.1038/sj.onc.1210955
Abstract
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 |
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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: | Unnamed user with email elements@essex.ac.uk |
Depositing User: | Unnamed user with email elements@essex.ac.uk |
Date Deposited: | 04 Dec 2013 12:30 |
Last Modified: | 07 Aug 2024 19:32 |
URI: | http://repository.essex.ac.uk/id/eprint/8302 |