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Reduced Circulating Insulin-like Growth Factor I Levels Delay the Onset of Chemically and Genetically Induced Mammary Tumors

Section on Cellular and Molecular Physiology, Diabetes Branch [Y. W., J. S., D. L., S. Y.] and Laboratory of Genetics and Physiology [K. C., K. M., L. H.], National Institutes of Diabetes, Digestive and Kidney Diseases, and Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute [J. E. G.], NIH, Bethesda, Maryland 20892

Insulin-like growth factors (IGFs) play a crucial role in regulating cell proliferation and differentiation. The aim of this study was to examine the potential relationship between serum IGF-I levels and breast cancer risk. To do this, we studied liver-specific IGF-I gene-deleted (LID) mice, in which circulating IGF-I levels are 25% of that in control mice. Mammary tumors were induced in two ways: (a) by exposing mice to the carcinogen 7,12-dimethybenz (a)anthracene; and (b) by crossing LID mice with C3(1)/SV40 large T-antigen transgenic mice. In both models, LID mice exhibited a delayed latency period of mammary tumor development. In the 7,12-dimethybenz (a)anthracene-induced mammary tumor model, the incidence of palpable mammary tumors was significantly lower in LID mice (26% versus 56% in controls), and the onset of the tumors was delayed (74 ± 1.2 days in LID mice versus 59.5 ± 1.1 days in controls). Histological analysis showed extensive squamous metaplasia in late-stage mammary tumors of control mice, whereas late-stage tumors from LID mice exhibited extensive hyperplasia, but little metaplasia. In control mice, the onset of C3(1)/SV40-large T-antigen-induced mammary tumors occurred at 21.6 ± 1.8 weeks of age, whereas in LID mice the average age of onset was 30.2 ± 1.7 weeks. In addition, 60% of the mice in the control group developed two or more mammary tumors per mouse, whereas in the LID mice only 30% developed more than one mammary tumor per mouse. Our data demonstrate that circulating IGF-I levels play a significant role as a risk factor in the onset and development of mammary tumors in two well-established animal models of breast cancer.

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