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

Oncogene volume 27, pages 2941–2950 (2008)Cite this article

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.

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Acknowledgements

We are grateful to Simak Ali and to members of the Androgen Signalling Laboratory for extensive discussion and criticism and for technical help. This study was supported by the Medical Research Council and the Hammersmith Hospitals Trust Research Committee and CB was supported by a grant from the Prostate Cancer Charity.

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Authors and Affiliations

  1. Department of Oncology, Androgen Signalling Laboratory, Imperial College London, London, UK

    G N Brooke & C L Bevan

  2. Institute of Reproductive and Developmental Biology, Imperial College London, London, UK

    M G Parker

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  1. G N Brooke
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Correspondence to C L Bevan.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Brooke, G., Parker, M. & Bevan, C. Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression. Oncogene 27, 2941–2950 (2008). https://doi.org/10.1038/sj.onc.1210955

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