Aberrant BAF57 Signaling Facilitates Prometastatic Phenotypes
- Authors
- Balasubramaniam, Sucharitha; Comstock, Clay E. S.; Ertel, Adam; Jeong, Kwang Won; Stallcup, Michael R.; Addya, Sankar; McCue, Peter A.; Ostrander, William F., Jr.; Augello, Michael A.; Knudsen, Karen E.
- Issue Date
- 15-May-2013
- Publisher
- AMER ASSOC CANCER RESEARCH
- Citation
- CLINICAL CANCER RESEARCH, v.19, no.10, pp.2657 - 2667
- Journal Title
- CLINICAL CANCER RESEARCH
- Volume
- 19
- Number
- 10
- Start Page
- 2657
- End Page
- 2667
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/14541
- DOI
- 10.1158/1078-0432.CCR-12-3049
- ISSN
- 1078-0432
- 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. Experimental Design: 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 alpha 2 integrin upregulation, and altered other SWI/SNF complex components at the alpha 2 integrin locus. BAF57-dependent alpha 2 integrin induction conferred a prometastatic migratory advantage, which was attenuated by anti-alpha 2 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. (C) 2013 AACR.
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