Wu Yiping, Cui Karen, Miyoshi Keiko, Hennighausen Lothar, Green Jeffrey E, Setser Jennifer, LeRoith Derek, Yakar Shoshana
Section on Cellular and Molecular Physiology, Diabetes Branch, National Institute of Diabetes, Digestive and Kidney Diseases/NIH, Building 10, Bethesda, MD 20892, USA.
Cancer Res. 2003 Aug 1;63(15):4384-8.
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.
胰岛素样生长因子（IGFs）在调节细胞增殖和分化中起关键作用。本研究的目的是探讨血清IGF-I水平与乳腺癌风险之间的潜在关系。为此，我们研究了肝脏特异性IGF-I基因缺失（LID）小鼠，其循环IGF-I水平为对照小鼠的25%。通过两种方式诱导乳腺肿瘤：（a）将小鼠暴露于致癌物7,12-二甲基苯并（a）蒽；（b）将LID小鼠与C3(1)/SV40大T抗原转基因小鼠杂交。在两种模型中，LID小鼠的乳腺肿瘤发生潜伏期均延迟。在7,12-二甲基苯并（a）蒽诱导的乳腺肿瘤模型中，LID小鼠可触及乳腺肿瘤的发生率显著低于对照小鼠（26%对56%），且肿瘤发生延迟（LID小鼠为74±1.2天，对照小鼠为59.5±1.1天）。组织学分析显示，对照小鼠晚期乳腺肿瘤有广泛的鳞状化生，而LID小鼠的晚期肿瘤表现为广泛的增生，但化生较少。在对照小鼠中，C3(1)/SV40大T抗原诱导的乳腺肿瘤发病年龄为21.6±1.8周龄，而LID小鼠的平均发病年龄为30.2±1.7周龄。此外，对照组60%的小鼠每只发生两个或更多乳腺肿瘤，而LID小鼠中只有30%的小鼠每只发生一个以上乳腺肿瘤。我们的数据表明，在两种成熟的乳腺癌动物模型中，循环IGF-I水平作为一个风险因素在乳腺肿瘤的发生和发展中起重要作用。
