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) 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...

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Bibliographic Details
Published in:Clinical cancer research 1999-02, Vol.5 (2), p.405-411
Main Authors: CONTESSA, J. N, REARDON, D. B, TODD, D, DENT, P, MIKKELSEN, R. B, VALERIE, K, BOWERS, G. D, SCHMIDT-ULLRICH, R. K
Format: Article
Language:English
Subjects:
Biological and medical sciences
Breast Neoplasms
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Cell Division - drug effects
Cell Division - radiation effects
Dose-Response Relationship, Drug
Doxycycline - pharmacology
Female
Gene Deletion
Gynecology. Andrology. Obstetrics
Humans
Kinetics
Mammary gland diseases
Medical sciences
Radiation Tolerance
Receptor, Epidermal Growth Factor - biosynthesis
Receptor, Epidermal Growth Factor - genetics
RNA, Messenger - biosynthesis
Tumor Cells, Cultured
Tumors
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Summary: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.
ISSN:1078-0432
1557-3265