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Angiogenesis, Metastasis, and the Cellular Microenvironment

Involvement of the Chemokine Receptor CXCR4 and Its Ligand Stromal Cell-Derived Factor 1 in Breast Cancer Cell Migration Through Human Brain Microvascular Endothelial Cells¹

Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Hava Karsenty Avraham, Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115. Phone: (617) 667-0073; Fax: (617) 975-6373. E-mail: havraham{at}bidmc.harvard.edu

In this study, we have characterized the signaling pathways mediated by CXCR4 in breast cancer cells and its role in breast cancer cell invasion and migration. Stromal cell-derived factor 1 (SDF-1; CXCL12) stimulation of breast cancer cells resulted in phosphoinositide 3-kinase (PI-3K) activation, AKT phosphorylation, and activation of the FKHRL1 transcription factor. In addition, SDF-1 induced activation of the focal adhesion kinase (FAK) as well as the migration of breast cancer cells. Expression of SDF-1, the ligand of CXCR4, was about 2-fold higher in microdissected human breast epithelial cancer cells as compared with normal epithelial cells. Immunohistochemical analysis indicated that SDF-1 expression is consistently higher in primary breast tumor cells than in normal breast epithelial cells. Furthermore, SDF-1 induced blood vessel instability, through increased vascular permeability, resulting in the penetration of breast tumor cells through the human brain microvascular endothelial cells (HBMEC). Notably, the migration of breast cancer cells was inhibited by the PI-3K inhibitor, Wortmannin, and the Ca²⁺ inhibitor BAPTA/AM, indicating that transendothelial breast cancer cell migration induced by SDF-1 is mediated by activation of the PI-3K/AKT pathway and Ca²⁺-mediated signaling. Blockade of the CXCR4/SDF1 signaling pathway with anti-CXCR4 antibody also decreased transendothelial breast cancer cell migration as well as vascular permeability. This study focuses on novel interactions between highly relevant signaling pathways in breast cancer cells and brain microvascular endothelial cells and may provide insights into the molecular mechanisms of CXCR4/SDF-1-mediated breast cancer metastasis to the brain.

Key Words: SDF-1 • CXCR4 • migration • signaling • metastasis • breast cancer

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