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CXCL-12/stromal cell-derived factor-1alpha transactivates HER2-neu in breast cancer cells by a novel pathway involving Src kinase activation.

Cabioglu N, Summy J, Miller C, Parikh NU, Sahin AA, Tuzlali S, Pumiglia K, Gallick GE, Price JE

Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

Experimental evidence suggests that CXCR4, a Gi protein-coupled receptor for the ligand CXCL12/stromal cell-derived factor-1alpha (SDF-1alpha), 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-1alpha 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-1alpha-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-1alpha-stimulated cell migration. We report a novel mechanism of HER2-neu transactivation through SDF-1alpha stimulation of CXCR4 that involves Src kinase activation.

Published 2 August 2005 in Cancer Res, 65(15): 6493-7.
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