Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor Journal Article

   

Authors:	Watson, P. A.; Chen, Y. F.; Balbas, M. D.; Wongvipat, J.; Socci, N. D.; Viale, A.; Kim, K.; Sawyers, C. L.
Article Title:	Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor
Abstract:	Androgen receptor (AR) splice variants lacking the ligand binding domain (ARVs), originally isolated from prostate cancer cell lines derived from a single patient, are detected in normal and malignant human prostate tissue, with the highest levels observed in late stage, castration-resistant prostate cancer. The most studied variant (called AR-V7 or AR3) activates AR reporter genes in the absence of ligand and therefore, could play a role in castration resistance. To explore the range of potential ARVs, we screened additional human and murine prostate cancer models using conventional and next generation sequencing technologies and detected several structurally diverse AR isoforms. Some, like AR-V7/AR3, display gain of function, whereas others have dominant interfering activity. We also find that ARV expression increases acutely in response to androgen withdrawal, is suppressed by testosterone, and in some models, is coupled to full-length AR (AR-FL) mRNA production. As expected, constitutively active, ligand-independent ARVs such as AR-V7/AR3 are sufficient to confer anchorage-independent (in vitro) and castration-resistant (in vivo) growth. Surprisingly, this growth is blocked by ligand binding domain-targeted antiandrogens, such as MDV3100, or by selective siRNA silencing of AR-FL, indicating that the growth-promoting effects of ARVs are mediated through AR-FL. These data indicate that the increase in ARV expressionin castrate-resistant prostate cancer is an acute response to castration rather than clonal expansion of castration or antiandrogen-resistant cells expressing gain of function ARVs, and furthermore, they provide a strategy to overcome ARV function in the clinic.
Keywords:	human cell; sequence analysis; exons; cancer growth; nonhuman; protein domain; animal cell; mouse; animals; mice; gene expression; animal experiment; animal model; small interfering rna; gene function; rna interference; cell line, tumor; cancer resistance; prostate cancer; prostatic neoplasms; gene expression regulation, neoplastic; amino acid sequence; molecular sequence data; messenger rna; rna, messenger; alternative splicing; murinae; androgen receptor; protein structure, tertiary; antiandrogen; castration; receptors, androgen; disease models, animal; testosterone; anchorage independent growth; androgens; sequence analysis, protein; splicing defect
Journal Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	107
Issue:	39
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Date Published:	2010-09-28
Start Page:	16759
End Page:	16765
Language:	English
DOI:	10.1073/pnas.1012443107
PUBMED:	20823238
PROVIDER:	scopus
PMCID:	PMC2947883
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-78049280194&partnerID=40&md5=ba5527442fa1a75d91a6857e1f3a1e3f
Notes:	--- - "Cited By (since 1996): 5" - "Export Date: 20 April 2011" - "CODEN: PNASA" - "Source: Scopus"

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