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Insulin-like Growth Factor-I Receptor Overexpression Mediates Cellular Radioresistance and Local Breast Cancer Recurrence after Lumpectomy and Radiation¹

Departments of Therapeutic Radiology [B. C. T., B. G. H., L. N., J. Y., P. A. H., A. A. G., P. M. G.] and Pathology [L. K., D. C.], Yale University School of Medicine, New Haven, Connecticut 06520-8040; Jefferson Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-5541 [J-L. B., R. B.]

The insulin-like growth factor-I receptor (IGF-IR) plays a critical role in cell growth regulation and transformation. The radiosensitivity of NIH 3T3 fibroblasts overexpressing either wild-type or mutant IGF-IR was examined. High levels of wild-type IGF-IR conferred radioresistance, and mutational analysis revealed that this effect correlated with the transforming capacity but not the mitogenic activity of the receptor. The radioresistant phenotype was reversed when the cells were incubated with antisense oligonucleotides targeted to IGF-IR mRNA, demonstrating that IGF-IR directly influences radioresistance. The clinical significance of these findings was examined in an immunohistochemical analysis of primary breast tumors, revealing that high levels of IGF-IR in tumor samples were highly correlated with ipsilateral breast tumor recurrence (IBTR) following lumpectomy and radiation therapy (P = 0.001). Subgroup analysis revealed that, for early breast tumor relapses (within 4 years of initial breast tumor diagnosis), elevated levels of IGF-IR were strongly associated with IBTR (P = 0.004) but IGF-IR expression was not prognostic for IBTR from breast cancer patients with late relapses (P was not significant). These studies provide evidence for the influence of IGF-IR on cellular radioresistance and response to therapy and raise the possibility that the radiocurability of selected tumors may be improved by pharmaceutical strategies directed toward the IGF-IR.

¹ This work was supported by the Yale University Department of Therapeutic Radiology, the Charles E. Culpeper Foundation, and NIH Grant ES05775.

² To whom requests for reprints should be addressed, at the Department of Therapeutic Radiology, Yale University School of Medicine, P. O. Box. 208040, New Haven, CT 06520-8040. Phone: (203) 737-2788; Fax: (203) 737-2630; E-mail: peter.glazer@qm.yale.edu.

Received 5/ 5/97. Accepted 6/10/97.

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