The difficulty in successfully treating advanced stage breast cancer contributes greatly to the 41,200 estimated deaths due to breast cancer this year. Even recent advances in therapies only improve the average survival of patients with advanced breast cancer from 20 months to 25 months. Therefore, the development of new therapeutics by identifying new targets is needed to improve the life span of these patients. Previously, two tyrosine kinases, the EGFR and c-Src, were demonstrated to be overexpressed in 24% and 70%, respectively, of breast cancer cell lines and tumors studied and correlating with advanced disease (3, 6, 18, 21). Although alone neither the EGFR nor c-Src have shown to directly contribute to the development of tumorigenesis, these molecules exhibit striking biological synergism when co-overexpressed (15). Specifically, this co-overexpression leads to tumorigenesis in nude mice and correlates with the novel phosphorylation at tyrosine 845 and 1101 on the EGFR in a mouse fibroblast model (5, 15). This proposal is designed to test the hypothesis that the synergistic interactions between co-overexpressed EGFR and c-Src is a contributing step in breast cancer tumongenesis by (1) testing the biological synergy of EGFR and c-Src in a transgenic mouse model of breast cancer, (2) determining the binding site on the EGFR for c-Src, and (3) analyzing the effect of peptides complementary to pY845 and the c-Src binding site on EGF-induced DNA synthesis, transformation, and tumorigenesis. A transgenic mouse model for breast cancer will be developed by crossing MMTV-EGFR transgenic mice with MMTV-c-Src transgenic mice and evaluating the mice for tumor formation. Deletion and point mutants of the EGFR will be utilized to identify the binding site on the EGFR for c-Src. Peptides corresponding to pY845 or the c-Src binding site on the EGFR will be adminstered into tumors xenografted onto nude mice to study the ability of the peptides to inhibit tumorigenesis.
| Boerner, Julie L; Biscardi, Jacqueline S; Silva, Corinne M et al. (2005) Transactivating agonists of the EGF receptor require Tyr 845 phosphorylation for induction of DNA synthesis. Mol Carcinog 44:262-73 |
| Boerner, Julie L; Gibson, Matthew A; Fox, Emily M et al. (2005) Estrogen negatively regulates epidermal growth factor (EGF)-mediated signal transducer and activator of transcription 5 signaling in human EGF family receptor-overexpressing breast cancer cells. Mol Endocrinol 19:2660-70 |
| Boerner, Julie L; Demory, Michelle L; Silva, Corinne et al. (2004) Phosphorylation of Y845 on the epidermal growth factor receptor mediates binding to the mitochondrial protein cytochrome c oxidase subunit II. Mol Cell Biol 24:7059-71 |
