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Insulin Receptor Levels and Magnitude of Insulin-induced Responses in 7,12-Dimethylbenz(a)anthracene-induced Mammary Tumors in Rats¹

Department of Biochemistry [S. M. S., R. H.] and University of Rochester Cancer Center [R. H.], University of Rochester School of Medicine and Dentis Rochester, New York 14642

The majority of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors are insulin dependent and regress when the host is made diabetic with streptozotocin. Treatment of diabetic rats with insulin (8 IU insulin per day per rat for 8 days) normalized blood and urinary glucose and reactivated growth of 11 of 15 regressing tumors. Insulin-dependent tumors demonstrated 3-fold-higher ¹²⁵I-labeled insulin binding than did insulin-independent neoplasms, which grow in diabetic hosts. Insulin binding to enzymatically dissociated tumor cells maintained in culture for 3 days was also 3-fold higher in cells from insulin-dependent tumors. In cells cultured in vitro in Medium 199, 4% calf serum and 5 x 10^-10 M insulin were the minimal levels of these components compatible with maximal precursor incorporation into macromolecules; subsequent experiments utilized these conditions. The time course of precursor incorporation, as influenced by insulin in vitro, was observed for 5 min to 24 hr in dependent versus independent tumor cell cultures. For dependent cells, insulin stimulated thymidine incorporation 1.25-fold above that of the control at 2 hr and reached a maximum of 2.15-fold by 10 hr. Stimulation of uridine incorporation by insulin (2.55-fold increase) was maximal at 6 hr, and leucine incorporation (1.7-fold increase) was maximal at 12 hr. Insulin stimulation of thymidine incorporation in cells from independent tumors was also maximal by 10 hr, but it demonstrated no more than 1.21-fold increase even with insulin additions as high as 10^-6 M; uridine incorporation was stimulated by 1.40-fold, and leucine incorporation, by 1.15-fold. These studies add further support for the role of insulin in growth regulation of mammary cancer, and they suggest a relationship between insulin binding and magnitude of biological response.

¹ Supported by Grant CA 16660 from the USPHS, NIH.

² Present address: Laboratory of Pathophysiology, Building 10, Room B1B37, National Cancer Institute, NIH, Bethesda, Md. 20205.

³ To whom requests for reprints should be addressed.

Received 8/21/80. Accepted 11/25/80.