title: Aberrant BAF57 signaling facilitates prometastatic phenotypes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Sucharitha
authors.initials: S
authors.lastname: Balasubramaniam
authors.forename: Clay E S
authors.initials: CE
authors.lastname: Comstock
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Kwang Won
authors.initials: KW
authors.lastname: Jeong
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stallcup
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCue
authors.forename: William F
authors.initials: WF
authors.lastname: Ostrander
authors.forename: Michael A
authors.initials: MA
authors.lastname: Augello
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D039421:Integrin alpha2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D039421:Integrin alpha2; D011944:Receptors, Androgen; C504738:SMARCE1 protein, human