Abstract A69: aB-crystallin: A novel regulator of breast cancer metastasis to the brain

Abstract

Abstract Brain metastases are a devastating complication of advanced breast cancer that result in disabling neurologic deficits and death within one year in the vast majority of patients. Triple-negative breast tumors, which lack expression of the estrogen receptor, progesterone receptor and HER2, commonly metastasize to the brain. However, the genes regulating brain metastasis are poorly understood. The molecular chaperone aB-crystallin is frequently expressed in triple-negative breast cancer and has been reported to play important roles in cytoskeletal organization, cell migration and invasion. As such, we hypothesized that aB-crystallin promotes metastasis in triple-negative breast cancer. To test this hypothesis, we stably overexpressed aB-crystallin in triple-negative breast cancer cells with low endogenous expression of the protein and stably silenced aB-crystallin in triple-negative breast cancer cells with high endogenous levels. We examined the effects of altering aB-crystallin levels on adhesion to human brain microvascular endothelial cells (HBMECs) and penetration of an in vitro model of the blood-brain barrier (BBB). In addition, orthotopic models of triple-negative breast cancer in which fluorescently labeled breast cancer cells metastasize from the mammary gland to the brain were utilized to evaluate the effects of aB-crystallin on primary and metastatic tumor burden in vivo. We observed that silencing aB-crystallin inhibited adhesion to HBMECs and penetration of an in vitro BBB model, while overexpression of aB-crystallin enhanced adhesion to HBMECs and penetration of the BBB in vitro. Consistent with these results, overexpression of aB-crystallin in triple-negative breast cancer cells increased brain metastasis in female NSG mice with transplanted mammary tumors, while silencing aB-crystallin inhibited brain metastasis. We also demonstrated that aB-crystallin enhanced adhesion to HBMECs by a b1 integrin-dependent mechanism. Taken together, our results point to a novel role of aB-crystallin in breast cancer brain metastasis and suggest that aB-crystallin may be a promising drug target for this rapidly fatal disease. Citation Format: Dmitry Malin, Elena Strekalova, Andrey Ugolkov, Vladimir Petrovic, Vincent Cryns. aB-crystallin: A novel regulator of breast cancer metastasis to the brain. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A69.