Human Cancer Biology aB-Crystallin: ANovelRegulatorofBreastCancerMetastasis to the Brain

Purpose: 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 aB-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 aB-crystallin in brain metastasis in TNBCs. Experimental Design: aB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brainmetastases. aB-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 silencingaB-crystallin on brainmetastasis in vivowere investigated using orthotopic TNBC models. Results: In a cohort of women with breast cancer brain metastasis, aB-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 aB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing aB-crystallin inhibited these events. aB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through ana3b1 integrin–dependentmechanism.aB-crystallin overexpression promoted brainmetastasis, whereas silencing aB-crystallin inhibited brain metastasis in orthotopic TNBC models. Conclusion: aB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease. Clin Cancer Res; 1–12. 2013 AACR.