The inducible expression of dominant-negative epidermal growth factor receptor-CD533 results in radiosensitization of human mammary carcinoma cells

Ionizing radiation activates the epidermal growth factor receptor (EGFR) an d downstream signaling involving the cytoprotective mitogen-activated prote in 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-C D533, a truncated EGFR mutant lacking mitogenic and transformation activity , EGFR-CD533 expression inhibits radiation- and EGF-induced EGFR autophosph orylation and MAPK activation and, therefore, functions as a dominant-negat ive mutant without blocking the expression of EGFR or erbB-2, another membe r of the erbB receptor Tyr kinase family. Expression of EGFR-CD533 only min imally inhibited cell growth and did not alter radiosensitivity to single r adiation exposures. However, repeated 2 Gy radiation exposures of cells, un der conditions of EGFR-CD533 expression, essentially abolished their abilit y 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 radiosenisitization of ce lls by counteracting a radiation-induced cytoprotective proliferation respo nse.