Abstract 2911: EGFR and c-Src crosstalk in breast cancer cell migration
Authors: Kelly L. Mueller, Julie L. Boerner
Journal: Cancer Research (2011)

Abstract Patients with breast cancer do not respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in the clinic, although 56% of basal breast cancers overexpress EGFR. These observations suggest that inhibiting EGFR kinase activity is insufficient to abrogate tumor growth. Therefore, the contribution of EGFR overexpression in breast cancer remains unknown. Recently, the increased activation of other tyrosine kinases, such as Met and c-Src, has been shown to contribute to cellular responses to EGFR inhibitors. The non-receptor tyrosine kinase c-Src is overexpressed in 70% of breast cancers, yet like EGFR, its role in breast cancer tumorigenesis has not fully been elucidated. Using cell culture models, co-overexpression of EGFR and c-Src has been shown to enhance proliferation, transformation, and tumorigenesis. In addition, we have shown that inhibiting EGFR and c-Src kinase activities in combination results in a synergistic decrease in cell viability. Therefore, EGFR cooperativity with other kinases may mediate continued tumor growth and viability in breast cancer. The role of EGFR and c-Src co-overexpression in breast cancer metastasis remains unknown. Metastasis is a multi-step process that involves migration of tumor cells away from the primary tumor site. Here we present data demonstrating that when EGFR and c-Src are co-overexpressed in breast cancer cells (either endogenously or by inducible overexpression) there is an increase in EGF driven chemotactic cell migration. Interestingly, this EGF-induced increase in cell migration is dependent on the kinase activity of EGFR and c-Src, such that inhibition of either EGFR or c-Src kinase activity abrogates EGF-induced migration. This is in contrast to viability assays using the same cell lines where inhibiting EGFR kinase activity is insufficient to abrogate viability in EGFR/c-Src co-expressing cells. EGFR and c-Src crosstalk has been shown to result in the phosphorylation of EGFR on tyrosine 845. Tyrosine 845 on EGFR is not an autophosphorylation site and unlike other tyrosine residues found in the activation loops of tyrosine kinases, tyrosine 845 phosphorylation is not required for kinase activity, although it is required for EGFR/c-Src induced proliferation. In the EGFR and c-Src co-overexpressing breast cancer cell lines, treatment with either EGFR or c-Src kinase inhibitors led to a reduction in the phosphorylation on EGFR at tyrosine 845, correlating with the loss of EGF-mediated migration. In addition, mutation of tyrosine 845 on EGFR to a phenylalanine inhibited EGF-induced cell migration. These data suggest a role for Y845-EGFR phosphorylation in EGF-induced cell migration in EGFR/c-Src co-overexpressing breast cancer cells. In summary, we demonstrate that inhibiting either EGFR or c-Src kinase activity may be an effective way reduced breast cancer cell migration and abrogate metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2911. doi:10.1158/1538-7445.AM2011-2911