Sarah (Sally) J. Parsons, PhD
The Src proto-oncogene and EGF Receptor in breast and prostate cancer
The Epidermal Growth Factor Receptor (EGFR) is overexpressed in a large number of cancers, including breast, prostate, lung, head and neck, and colon, and is an indicator of poor prognosis in many of these diseases. The non-receptor tyrosine kinase, c-Src, is also overexpressed in many of the same types of cancers, suggesting that the two proteins may functionally interact to promote tumor progression. The Parsons laboratory has uncovered a novel mechanism by which these two proteins interact, which involves physical association as well as phosphorylation by c-Src of a unique site on the EGFR, namely, Tyr 845. This site is located in the catalytic domain of the receptor, but its phosphorylation has no effect on the receptor's kinase activity or signaling to Shc or MAP kinase. However, phospho-Tyr 845 (pY845) is required for EGF-induced proliferation and enhances EGF-mediated cell survival following apoptotic stress with DNA damaging drugs. Thus, the interaction between c-Src and EGFR may play critical roles in therapeutic resistance as well as in tumor growth. Two important downstream effectors of pY845 have been identified, namely, the transcription factor Stat5b, which is necessary for EGF-induced proliferation, and the mitochondrial enzyme, cytochrome c oxidase II (Cox II), which is strongly implicated as a regulator of apoptosis. In these signaling pathways, pY845 functions as a protein interaction domain, thus offering an alternative therapeutic target for the EGFR, in addition to its kinase domain. Currently, the role of pY845 and its proliferative and survival pathways in breast, prostate, and smooth muscle tumors of the uterus are under investigation in the lab and in collaboration with members of the Cell Signaling (A. Bouton, M. Brown), Endocrine (M. Shupnik, C. Silva, T. Guise, J. Chirgwin), Molecular Genetics (R. Li), and Mechanistic Developmental Therapeutics Programs (H. Frierson, K. Atkins, L. Rice). The goals are to determine the breadth of involvement of pY845 in tumor progression and therapeutic resistance, as well as to develop a peptidomimetic drug that interdicts pY845 function. These studies have utilized the Biomolecular Research Facility for DNA sequencing, mass spectrometry, and peptide synthesis; the FACs Facility for cell cycle and surface marker analysis; SAMMIC for whole animal imaging of metastatic tumors; and the Center for Advanced Microscopy for three-color confocal microscopy.