Document Detail


Androgen receptor gene rearrangements: new perspectives on prostate cancer progression.
MedLine Citation:
PMID:  23410127     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The androgen receptor (AR) is a master regulator transcription factor in normal and cancerous prostate cells. Canonical AR activation requires binding of androgen ligand to the AR ligand binding domain, translocation to the nucleus, and transcriptional activation of AR target genes. This regulatory axis is targeted for systemic therapy of advanced prostate cancer. However, a new paradigm for AR activation in castration-resistant prostate cancer (CRPC) has emerged wherein alternative splicing of AR mRNA promotes synthesis of constitutively active AR variants that lack the AR ligand binding domain (LBD). Recent work has indicated that structural alteration of the AR gene locus represents a key mechanism by which alterations in AR mRNA splicing arise. In this review, we examine the role of truncated AR variants (ARVs) and their corresponding genomic origins in models of prostate cancer progression, as well as the challenges they pose to the current standard of prostate cancer therapies targeting the AR ligand binding domain. Since ARVs lack the COOH-terminal LBD, the genesis of these AR gene rearrangements and their resulting ARVs provides strong rationale for the pursuit of new avenues of therapeutic intervention targeted at the AR NH2-terminal domain. We further suggest that genomic events leading to ARV expression could act as novel biomarkers of disease progression that may guide the optimal use of current and next-generation AR-targeted therapy.
Authors:
Lucas J Brand; Scott M Dehm
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Review    
Journal Detail:
Title:  Current drug targets     Volume:  14     ISSN:  1873-5592     ISO Abbreviation:  Curr Drug Targets     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-09     Completed Date:  2014-01-30     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  100960531     Medline TA:  Curr Drug Targets     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  441-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Androgens / genetics,  metabolism
Disease Progression
Gene Rearrangement*
Genomic Structural Variation
Humans
Male
Prostatic Neoplasms / genetics*,  metabolism,  pathology*
Prostatic Neoplasms, Castration-Resistant / genetics,  metabolism,  pathology
Receptors, Androgen / genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
R01 CA174777/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/AR protein, human; 0/Androgens; 0/Receptors, Androgen
Comments/Corrections

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