Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors.
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.
Wu
Yiping
Y
Section on Cellular and Molecular Physiology, Diabetes Branch, National Institute of Diabetes, Digestive and Kidney Diseases/NIH, Building 10, Bethesda, MD 20892, USA.
Cui
Karen
K
Miyoshi
Keiko
K
Hennighausen
Lothar
L
Green
Jeffrey E
JE
Setser
Jennifer
J
LeRoith
Derek
D
Yakar
Shoshana
S
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D002273:Carcinogens; D004195:Disease Models, Animal; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000097:blood* / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D000952:Antigens, Polyomavirus Transforming; D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D016283:Proto-Oncogene Proteins p21(ras)