Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression.
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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Three ligand-binding domain mutations commonly found in patient tumors, H874Y, T877A, and T877S, impart additional capacity for androgen receptor binding to motifs associated with coregulator proteins and stimulate expression of AR target genes, in addition to being activated by selective AR modulators, antiandrogens, and other hormones, compared with wild-type AR.
“Three LBD mutations that are commonly found in patient tumors, H874Y, T877A, and T877S, impart additional capacity for AR binding to motifs associated with coregulator proteins as well as stimulating the expression of AR target genes in addition to being activated by selective AR modulators, antiandrogens, and other hormones when compared with the wild-type AR (73).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [73]
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The role of androgen receptor mutations in prostate cancer progression.
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“Nuclear AR binds both palindromic and direct repeats of DNA hexamers known as androgen response elements (AREs) to activate its gene expression program, and is further regulated through association with numerous protein cofactors that bind the NTD or LBD through LXXLL and related motifs (Brooke et al., 2008; Weikum et…”
BackgroundReebye, V., Querol Cano, L., Lavery, D. N., Brooke, G. N., Powell, S. M., Chotai, D., Walker, M. M., Whitaker, H. C., Wait, R., Hurst, H. C., et al. (2012) · Molecular Endocrinology · doi:10.1210/me.2012-1056 · Cited by 47 · see citing works
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- Authors
- Brooke, G. N., Parker, M. G., & Bevan, C. L.
- Affiliations
- Imperial College London (GB)
- Corresponding author
- Bevan, C L
- Venue
- Oncogene
- Published
- 2007-11-26
- Volume
- 27
- Issue
- 21
- Pages
- 2941-2950
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W1990930634
- Cited by
- 79
- References
- 55
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 2 · 2013: 6 · 2012: 7
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Open Access at Essex (University of Essex) (submittedVersion)
- Funders
- Medical Research Council
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- androgen receptor, advanced prostate cancer, androgen receptor mutations, coactivator recruitment, antiandrogen resistance, transcriptional regulation, target gene expression
- MeSH terms
- HeLa Cells, Humans, Male, Mutation, Prostatic Neoplasms, Receptors, Androgen, Transcriptional Activation, Gene Expression, Polymerase Chain Reaction, Chromatin Immunoprecipitation
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