Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer

Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant p...

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Bibliographic Details
Published in:Nature communications Vol. 7; no. 1; p. 13668
Main Authors: Henzler, Christine, Li, Yingming, Yang, Rendong, McBride, Terri, Ho, Yeung, Sprenger, Cynthia, Liu, Gang, Coleman, Ilsa, Lakely, Bryce, Li, Rui, Ma, Shihong, Landman, Sean R., Kumar, Vipin, Hwang, Tae Hyun, Raj, Ganesh V., Higano, Celestia S., Morrissey, Colm, Nelson, Peter S., Plymate, Stephen R., Dehm, Scott M.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 29.11.2016
Nature Publishing Group
Nature Portfolio
Subjects:
38
38/39
38/91
631/208/514/2256
631/208/69
692/4028/67/589/466
Alleles
Androgens
Cell Line, Tumor
Chromosomes, Human, Pair 11 - genetics
Clone Cells
Exons - genetics
Gene Dosage
Gene Expression Regulation, Neoplastic
Gene Rearrangement - genetics
Genome, Human
Geriatrics
Heterogeneity
Humanities and Social Sciences
Humans
Ligands
Male
Medical research
multidisciplinary
Mutation
Neoplasm Metastasis
Prostate cancer
Prostatic Neoplasms, Castration-Resistant - genetics
Receptors, Androgen - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Science
Science (multidisciplinary)
Tumors
Urology
United States > US
Texas
Minnesota
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Description
Summary:Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements ( AR -GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR -GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR -GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR -GSRs as important drivers of persistent AR signalling in CRPC. Castration-resistant prostate cancer frequently presents with persistent androgen receptor signalling. Here, the authors find that the androgen receptor is subject to genetic rearrangements, resulting in variants with ligand-independent activity.
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These authors contributed equally to this work
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms13668