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

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The sentinel lymph node (SLN) is the only focus of axillary metastasis in a significant proportion of patients. In this single institutional study, clinicopathologic characteristics were investigated to determine the factors predicting the status of a SLN biopsy and the metastatic involvement of non-SLNs. Data were retrospectively reveiwed for 400 consecutive patients with clinical T1/T2 N0 breast cancer who underwent a SLN biopsy including axillary and/or internal mammary lymph nodes. The SLNs were evaluated by using the new AJCC staging criteria following multiple sectioning and immunohistochemical (IHC) analyses of nodes. The SLN contained metastases in 148 patients (38.5%) including 18 patients (12.2%) with micrometastases (0.2 cm). Five patients had isolated tumor cells detected by IHC (