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Cited by 185Prostate Cancer Treatment and ResearchProstate Cancer Diagnosis and TreatmentChromatin Remodeling and Cancer

The DOI matches its Crossref record; 85 of the 85 references it cites were found in a registry or an index.

The role of androgen receptor mutations in prostate cancer progression.

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Brooke, G., Bevan, C.·2009·Current Genomics
DOI 10.2174/138920209787581307PMC PMC2699836
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Abstract

Prostate tumour growth is almost always dependent upon the androgen receptor pathway and hence therapies aimed at blocking this signalling axis are useful tools in the management of this disease. Unfortunately such therapies invariably fail; and the tumour progresses to an "androgen-independent" stage. In such cases androgen receptor expression is almost always maintained and much evidence exists to suggest that it may still be driving growth. One mechanism by which the receptor is thought to remain active is mutation. This review summarises the present data on androgen receptor mutations in prostate cancer, and how such substitutions offer a growth advantage by affecting cofactor interactions or by reducing ligand specificity. Such alterations appear to have a subsequent effect upon gene expression suggesting that tumours may "behave" differently dependent upon the ligand promoting growth and if a mutation is present.

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Crossref · 10.2174/138920209787581307

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Figures

Fig. (1) Frequency and location of androgen receptor mutations associated with prostate cancer. The location and frequency of different single base mutations are given, highlighting where these substitutions lie in relation to functional domains of the androgen receptor.
Fig. (1) Frequency and location of androgen receptor mutations associated with prostate cancer. The location and frequency of different single base mutations are given, highlighting where these substitutions lie in relation to functional domains of the androgen receptor.CC BY · PubMed Central
Fig. (2) Hormone therapy failure caused by AR mutation. (1) The unliganded AR exists in the cytoplasm associated with a large heterocomplex that holds it in a ligand binding competent state. (2) Upon ligand binding the receptor dimerises, translocates to the nucleus where it binds DNA and promotes gene transcription via the recruitment of accessory proteins, such as coactivators. (3) Non organ-confined prostate cancer is usually treated by blocking the AR pathway. This is achieved by blocking the production of androgen (using LHRH analogues) and/or antiandrogens. (4) Antiandrogens bind to the AR but do not promote an active conformation and instead block receptor function, at least in part, by promoting the recruitment of corepressors to the regulatory regions of target genes. (5) This therapy selects for cells that have mechanisms by which the tumour can grow in the androgen depleted environment. One such mechanism is that of AR mutation and in some cases these mutants provide a growth advantage because they reduce the ligand specificity of the receptor. Hence other ligands, such as the antiandrogens being used in treatment, are now able to promote an active conformation, the recruitment of coactivators and subsequently gene expression.
Fig. (2) Hormone therapy failure caused by AR mutation. (1) The unliganded AR exists in the cytoplasm associated with a large heterocomplex that holds it in a ligand binding competent state. (2) Upon ligand binding the receptor dimerises, translocates to the nucleus where it binds DNA and promotes gene transcription via the recruitment of accessory proteins, such as coactivators. (3) Non organ-confined prostate cancer is usually treated by blocking the AR pathway. This is achieved by blocking the production of androgen (using LHRH analogues) and/or antiandrogens. (4) Antiandrogens bind to the AR but do not promote an active conformation and instead block receptor function, at least in part, by promoting the recruitment of corepressors to the regulatory regions of target genes. (5) This therapy selects for cells that have mechanisms by which the tumour can grow in the androgen depleted environment. One such mechanism is that of AR mutation and in some cases these mutants provide a growth advantage because they reduce the ligand specificity of the receptor. Hence other ligands, such as the antiandrogens being used in treatment, are now able to promote an active conformation, the recruitment of coactivators and subsequently gene expression.CC BY · PubMed Central
Fig. (3) Surface representation of the AR coactivator groove. Representation of the AR AF-2 surface highlighting the L-shaped cleft and key residues important in coactivator binding. +1, +4 and +5 refer to the regions in which the 1st, 4th and 5th amino acids of LxxLL and FxxLF-like motifs lie following binding. Image created using RasMol V2.6 using co-ordinates from [30].
Fig. (3) Surface representation of the AR coactivator groove. Representation of the AR AF-2 surface highlighting the L-shaped cleft and key residues important in coactivator binding. +1, +4 and +5 refer to the regions in which the 1st, 4th and 5th amino acids of LxxLL and FxxLF-like motifs lie following binding. Image created using RasMol V2.6 using co-ordinates from [30].CC BY · PubMed Central

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Citations

Cites

Research works printed but not linked: 3

  1. [59]Brooks J Walsh P A.R Darracott Vaughan E Wein A Anatomy of the lower urinary tract and male genitalia Campbell's Urology 2002 London Saunders 41 80
  2. [64]Shepherd DL Harris M Thompson I Syrigos K Radical Prostatectomy in the management of localised prostate cancer Prostate Cancer: Biology, Diagnosis and Management 2001 Oxford Oxford University Press 229 242
  3. [72]Taplin M-E Bubley GJ Shuster TD Frantz ME Spooner AE Ogata GK Keer HN Balk SP Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer N. Engl. J. Med 1995 332 1393 1398 7723794

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Metadata

Authors
Brooke, G., & Bevan, C.
Affiliations
Imperial College London (GB)
Corresponding author
Bevan, C.
ORCID
Venue
Current Genomics
Publisher
Bentham Science Publishers Ltd.
Published
2009-03-01
Volume
10
Issue
1
Pages
18-25
ISSN
1389-2029 (ISSN-L)
DOI
10.2174/138920209787581307
PMC
PMC2699836
OpenAlex
W2082107721
Cited by
181
References
83
Citations by year
2026: 4 · 2025: 8 · 2024: 5 · 2023: 8 · 2022: 7 · 2021: 12 · 2020: 11 · 2019: 8 · 2018: 14 · 2017: 7 · 2016: 11 · 2015: 17 · 2014: 13 · 2013: 12 · 2012: 12
FWCI
12.39
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Current Genomics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Open Access at Essex (University of Essex) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
  • Health Sciences › Medicine › Urology › Prostate Cancer Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
androgen receptor, androgen receptor mutations, prostate cancer progression, castration-resistant prostate cancer, androgen receptor signaling, cofactor interactions, ligand specificity, gene expression, androgen receptor antagonists

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