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The Inducible Expression of Dominant-Negative Epidermal Growth Factor Receptor-CD533 Results in Radiosensitization of Human Mammary Carcinoma Cells¹

Departments of Radiation Oncology [J. N. C., D. B. R., D. T., R. B. M., K. V., G. D. B., R. K. S-U.] and Pharmacology [P. D.], Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298

ABSTRACT

Ionizing radiation activates the epidermal growth factor receptor (EGFR) and downstream signaling involving the cytoprotective mitogen-activated protein kinase (MAPK) pathway. In our effort to investigate the role of EGFR in cellular responses to radiation, we generated mammary carcinoma cell clones, MCF-TR5-EGFR-CD533 and MDA-TR15-EGFR-CD533, that inducibly express EGFR-CD533, a truncated EGFR mutant lacking mitogenic and transformation activity. EGFR-CD533 expression inhibits radiation- and EGF-induced EGFR autophosphorylation and MAPK activation and, therefore, functions as a dominant-negative mutant without blocking the expression of EGFR or erbB-2, another member of the erbB receptor Tyr kinase family. Expression of EGFR-CD533 only minimally inhibited cell growth and did not alter radiosensitivity to single radiation exposures. However, repeated 2 Gy radiation exposures of cells, under conditions of EGFR-CD533 expression, essentially abolished their ability for subsequent cell growth. These results identify the inhibition of EGFR function through genetic manipulation as a potential therapeutic maneuver. The concept of such an intervention would be the radiosensitization of cells by counteracting a radiation-induced cytoprotective proliferation response.

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