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Department of Medicine, Division of Endocrinology and Metabolism [J. L. R., D. B. R., K. H., N. J. G. W., B. L. S.] and the Cancer Center [N. J. G. W.], University of California, San Diego, La Jolla, California 92093, and the Medical Research Service, Department of Veterans Affairs Medical Center, San Diego, California 92161 [N. J. G. W., B. L. S.]
Insulin-like growth factor I action has been implicated in the pathogenesis of many different malignancies, including breast cancer. Insulin-like growth factor I receptors (IGF-IRs) are overexpressed in virtually all breast cancer cell lines, in which they are believed to enhance growth and inhibit apoptosis. In this study, the functional activity of IGF-IRs from normal and malignant human breast tissue was assessed. IGF-IR expression was 14-fold higher in malignant breast tissue than in normal breast tissue. IGF-IR autophosphorylation and kinase activity were 2–4-fold higher in purified receptor preparations from malignant breast tissue as compared to normal breast tissue when normalized for receptor number. This increase in receptor function, coupled with the enhanced receptor expression, amounts to a 40-fold elevation in IGF-IR tyrosine kinase activity in malignant breast tissue. The enhanced receptor autophosphorylation and kinase activity were observed in the absence of hormonal stimulation and seem to result from an alteration in the intrinsic activity of the receptor itself. Protein tyrosine phosphatase activity is also increased in malignant breast tissue. These data suggest that the IGF-IR is an important target for breast cancer therapy.
1 Supported by NIH Grants DK44643 (to N. J. G. W.) and DK02162 (to B. L. S.), the Sam and Rose Stein Institute for Research on Aging (B. L. S.), the Department of Veterans Affairs (N. J. G. W.), and the American Diabetes Association (N. J. G. W.). N. J. G. W. is a faculty member of the University of California at San Diego Biomedical Sciences Graduate Program. B. L. S. was a faculty member in the University of California at San Diego Department of Medicine, Division of Endocrinology and Metabolism.
2 To whom requests for reprints should be addressed, at Department of Medicine (0673), University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0673. Phone: (619) 534-6275; Fax: (619) 534-7181; E-mail: nwebster@ucsd.edu.
Received 9/ 2/97. Accepted 1/ 9/98.
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