Aberrant BAF57 signaling facilitates prometastatic phenotypes.
Clin Cancer Res
; 19(10): 2657-67, 2013 May 15.
Article
em En
| MEDLINE
| ID: mdl-23493350
ABSTRACT
PURPOSE:
BAF57, a component of the switching-defective and sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex conglomerate, modulates androgen receptor activity to promote prostate cancer. However, the molecular consequences of tumor-associated BAF57 expression have remained undefined in advanced disease such as castration-resistant prostate cancer and/or metastasis. EXPERIMENTALDESIGN:
Clinical human specimens of primary and metastatic prostate cancer were immunohistochemically examined for tumor-grade association of BAF57 expression. Global gene expression analyses were conducted in models mimicking tumor-associated BAF57 expression. Aberrant BAF57-dependent gene expression changes, bypass of androgen-mediated signaling, and chromatin-specific SWI/SNF complex alterations with respect to cytoskeletal remodelers such as integrins were validated. Cell migration assays were used to profile the biologic phenotypes conferred under conditions simulating tumor-derived BAF57 expression.RESULTS:
Immunohistochemical quantitation of primary human specimens revealed that BAF57 was significantly and aberrantly elevated as a function of tumor grade. Critically, gene expression analyses showed that BAF57 deregulation circumvented androgen-mediated signaling, elicited α2 integrin upregulation, and altered other SWI/SNF complex components at the α2 integrin locus. BAF57-dependent α2 integrin induction conferred a prometastatic migratory advantage, which was attenuated by anti-α2 integrin antibody blockade. Furthermore, BAF57 was found to be markedly upregulated in human prostate cancer metastases of the lung, lymph node, and dura.CONCLUSION:
The findings herein, identifying tumor-associated BAF57 perturbation as a means to bypass androgen-signaling events that facilitate novel prometastatic phenotypes, link BAF57 upregulation to tumor dissemination. These data thereby establish BAF57 as a putative marker of metastatic potential that could be leveraged for therapeutic intervention.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
/
Proteínas Cromossômicas não Histona
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Regulação Neoplásica da Expressão Gênica
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Perfilação da Expressão Gênica
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Proteínas de Ligação a DNA
Tipo de estudo:
Prognostic_studies
Limite:
Humans
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Male
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article