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

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