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CXCL-12/Stromal Cell–Derived Factor-1 Transactivates HER2-neu in Breast Cancer Cells by a Novel Pathway Involving Src Kinase Activation

Departments of ¹ Cancer Biology and ² Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; ³ Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; and ⁴ Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York

Requests for reprints: Janet E. Price, Department of Cancer Biology, Unit 173, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-5484; Fax: 713-792-8747; E-mail: jprice{at}mdanderson.org.

Experimental evidence suggests that CXCR4, a G_i protein–coupled receptor for the ligand CXCL12/stromal cell–derived factor-1 (SDF-1), plays a role in breast cancer metastasis. Transactivation of HER2-neu by G protein–coupled receptor activation has been reported as a ligand-independent mechanism of activating tyrosine kinase receptors. We found that SDF-1 transactivated HER2-neu in the breast cancer cell lines MDA-MB-361 and SKBR3, which express both CXCR4 and HER2-neu. AMD3100, a CXCR4 inhibitor, PKI 166, an epidermal growth factor receptor/HER2-neu tyrosine kinase inhibitor, and PP2, a Src kinase inhibitor, each blocked SDF-1–induced HER2-neu phosphorylation. Blocking Src kinase, with PP2 or using a kinase-inactive Src construct, and inhibiting epidermal growth factor receptor/HER2-neu signaling with PKI 166 each inhibited SDF-1–stimulated cell migration. We report a novel mechanism of HER2-neu transactivation through SDF-1 stimulation of CXCR4 that involves Src kinase activation.

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