Paracrine overexpression of insulin-like growth factor-1 enhances mammary tumorigenesis in vivo
Paracrine overexpression of insulin-like growth factor-1 enhances mammary tumorigenesis in vivo
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DOI：
10.2353/ajpath.2008.071005
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发表时间：
2008-09-01
影响因子：
6
通讯作者：
Fuchs-Young, Robin
中科院分区：
文献类型：
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作者：
de Ostrovich, Krisztina Kovacs;Lambertz, Isabel;Fuchs-Young, Robin
胰岛素样生长因子-1(IGF-1)刺激增殖，调节组织发育，防止细胞凋亡，并促进乳腺和其他器官的恶性表型。一些流行病学研究将循环中高水平的IGF-1与乳腺癌风险增加联系在一起。为了研究IGF-1在体内乳腺肿瘤发生中的作用，我们使用了转基因小鼠，其中IGF-1的过度表达是在牛角蛋白5(BK5)启动子的控制下，并针对包括乳腺在内的各种器官的肌上皮细胞或基底细胞。这个模型很好地概括了女性乳腺上皮细胞对间质IGF-1的旁分泌暴露。组织学上，转基因小鼠的乳腺增生和高度血管化。与野生型组织相比，青春期前转基因小鼠的乳腺组织显著地促进了导管的增殖，尽管这种差异在青春期后不再保持。转基因小鼠对乳腺癌的易感性也增加了，74%的BK5。用7，12-二甲基苯并[a]蒽(每天20微克)处理的IGF-1小鼠发生了乳腺肿瘤，而野生型小鼠的这一比例为29%。有趣的是，31%的接受BK5.IGF-1治疗的动物自发患上乳腺癌，但没有野生型动物。乳腺肿瘤是中分化腺癌，在蛋白质和mRNA水平上都表达功能性的核雌激素受体。这些数据支持组织过表达IGF-1刺激乳腺肿瘤发生的假说。
Insulin-like growth factor-1 (IGF-1) stimulates proliferation, regulates tissue development, protects against apoptosis, and promotes the malignant phenotype in the breast and other organs. Some epidemiological studies have linked high circulating levels of IGF-1 with an increased risk of breast cancer. To study the role of IGF-1 in mammary tumorigenesis in vivo, we used transgenic mice in which overexpression of IGF-1 is under the control of the bovine keratin 5 (BK5) promoter and is directed to either the myoepithelial or basal cells in a variety of organs, including the mammary gland. This model closely recapitulates the paracrine exposure of breast epithelium to stromal IGF-1 seen in women. Histologically, mammary glands from transgenic mice were hyperplastic and highly vascularized. Mammary glands from prepubertal transgenic mice had significantly increased ductal proliferation compared with wildtype tissues, although this difference was not maintained after puberty. Transgenic mice also had increased susceptibility to mammary carcinogenesis, and 74% of the BK5.IGF-1 mice treated with 7,12-dimethylbenz[a]anthracene (20 mu g/day) developed mammary tumors compared with 29% of the wildtype mice. Interestingly, 31% of the vehicle-treated BK5.IGF-1 animals, but none of the wild-type animals, spontaneously developed mammary cancer. The mammary tumors were moderately differentiated adenocarcinomas that expressed functional, nuclear estrogen receptor at both the protein and mRNA levels. These data support the hypothesis that tissue overexpression of IGF-1 stimulates mammary tumorigenesis.