| Gene amplification and/or overexpression of c-Src and members of the Epidermal Growth Factor Receptor (EGFR/ErbB) family, which include EGFR, ErbB2, ErbB3, and ErbB4, have been detected in breast cancer. EGFR family members are implicated in breast cancer pathogenesis because they are both upregulated in breast cancer and receptor overexpression induces cellular transformation. Moreover, the increased presence of certain EGFR family members correlates with poor disease prognosis. In contrast, c-Src alone has a weak oncogenic potential. However, c-Src has been demonstrated to interact with EGFR family members, particularly EGFR and ErbB2. While c-Src has been demonstrated to augment the oncogenic signals of EGFR by many different cellular mechanisms, the exact relationship between c-Src and ErbB2, as well as ErbB3 and ErbB4, has not been well characterized.; This dissertation investigates the role of c-Src in modulating the physical and functional interaction between ErbB2 and ErbB3, two EGFR family members that preferentially associate with one another and exhibit the highest level of oncogenic potential of any possible dimers formed by EGFR family members. In contrast to kinase-inactive (K−) c-Src, wild type (wt) c-Src interacts with ErbB2 and ErbB3 in a ligand-independent fashion and enhances formation of the ErbB2/ErbB3 heterocomplex, resulting in increased receptor phosphorylation and activation of downstream signaling molecules, such as focal adhesion kinase and phosphatidylinositol-3 kinase. Furthermore, cellular motility and anchorage-independent growth promoted by the ErbB2/ErbB3 heterocomplex are dependent upon c-Src.; We also assessed whether c-Src may be an effective chemotherapeutic target in cancer. Both the in vitro and in vivo anchorage-independent growth of breast cancer cell lines was inhibited in a dose-dependent manner by Src family pharmacological inhibitors or K − c-Src. The dominant-negative activity of K− c-Src was found to localize to its Src-homology 2 (SH2) domain and carboxy-terminal half, but not to the Unique and SH3 domains. Furthermore, the amino-terminal lobe of the K− c-Src catalytic domain was determined to have negative effects on cell cycle progression. These results underscore the requirement for c-Src to maintain the oncogenic phenotype of breast cancer cells and identify a novel inhibitory activity for its carboxy-terminal half. |
