title: αB-crystallin: a novel regulator of breast cancer metastasis to the brain.
abstract: OBJECTIVE
  Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs.
  
  
  METHODS
  αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood-brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models.
  
  
  RESULTS
  In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin-dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models.
  
  
  CONCLUSIONS
  αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease.
authors.affiliation: Authors' Affiliations: Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health; Department of Chemical and Biological Engineering, University of Wisconsin, Madison, Wisconsin; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Breast Cancer Unit, Medical Oncology Department, Vall d'Hebron Institute of Oncology, Barcelona, Spain; Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois; Department of Pathology and Lab Medicine, Carolinas Medical Center, Charlotte, North Carolina; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Medicine and Department of Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Malin
authors.forename: Elena
authors.initials: E
authors.lastname: Strekalova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Petrovic
authors.forename: Allison M
authors.initials: AM
authors.lastname: Deal
authors.forename: Abraham
authors.initials: A
authors.lastname: Al Ahmad
authors.forename: Barbara
authors.initials: B
authors.lastname: Adamo
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.forename: Andrey
authors.initials: A
authors.lastname: Ugolkov
authors.forename: Chad
authors.initials: C
authors.lastname: Livasy
authors.forename: Karen
authors.initials: K
authors.lastname: Fritchie
authors.forename: Erika
authors.initials: E
authors.lastname: Hamilton
authors.forename: Kimberly
authors.initials: K
authors.lastname: Blackwell
authors.forename: Joseph
authors.initials: J
authors.lastname: Geradts
authors.forename: Matt
authors.initials: M
authors.lastname: Ewend
authors.forename: Lisa
authors.initials: L
authors.lastname: Carey
authors.forename: Eric V
authors.initials: EV
authors.lastname: Shusta
authors.forename: Carey K
authors.initials: CK
authors.lastname: Anders
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Cryns
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D057705:Transendothelial and Transepithelial Migration; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D038203:alpha-Crystallin B Chain / Q000502:physiology*
chemical_list: D038203:alpha-Crystallin B Chain