Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression.
Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression.
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作者：
Fierz Y;Novosyadlyy R;Vijayakumar A;Yakar S;LeRoith D
2型糖尿病增加了乳腺癌的风险和死亡率，高胰岛素血症已被确定为连接这两种疾病的主要因素。因此，我们假设药物降低升高的胰岛素水平将减弱2型糖尿病介导的乳腺肿瘤进展。我们研究了MKR+/+小鼠乳腺肿瘤的发展，MKR +/+小鼠是2型糖尿病的非肥胖、高胰岛素血症小鼠模型。将MKR+/+小鼠与乳腺特异性表达多瘤病毒中T癌基因的小鼠杂交，或原位接种小鼠乳腺肿瘤细胞系Met-1和MCNeuA。用CL-316243（一种特异性β3-肾上腺素能受体激动剂，可使胰岛素作用增敏，但对小鼠乳腺上皮或Met-1和MCNeuA细胞无直接影响）处理携带肿瘤的MKR+/+或对照小鼠。CL-316243给药显著降低了MKR+/+小鼠中升高的胰岛素水平，因此，在检测的三种肿瘤模型中减缓了乳腺肿瘤进展。这种作用伴随着转化乳腺组织中胰岛素和IGF-I受体磷酸化的减少。胰岛素增敏治疗足以消除2型糖尿病介导的乳腺肿瘤进展。因此，早期胰岛素增敏治疗可降低2型糖尿病患者的乳腺癌风险和死亡率。
Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia has been identified as a major factor linking these two diseases. Thus, we hypothesized that pharmacological reduction of elevated insulin levels would attenuate type 2 diabetes–mediated mammary tumor progression. We studied mammary tumor development in MKR+/+ mice, a nonobese, hyperinsulinemic mouse model of type 2 diabetes. MKR+/+ mice were either crossed with mice expressing the polyoma virus middle T oncogene specifically in the mammary gland or inoculated orthotopically with the mouse mammary tumor cell lines Met-1 and MCNeuA. MKR+/+ or control mice harboring tumors were treated with CL-316243, a specific β3-adrenergic receptor agonist, which sensitizes insulin action but has no direct effect on the mouse mammary epithelium or Met-1 and MCNeuA cells. CL-316243 treatment significantly reduced the elevated insulin levels in MKR+/+ mice and, as a consequence, attenuated mammary tumor progression in the three tumor models tested. This effect was accompanied by reductions in phosphorylation of insulin and IGF-I receptors in transformed mammary tissue. Insulin-sensitizing treatment is sufficient to abrogate type 2 diabetes–mediated mammary tumor progression. Therefore, early administration of insulin-sensitizing therapy may reduce breast cancer risk and mortality in patients with type 2 diabetes.
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影响因子：
56.9
作者：
EMORINE, LJ;MARULLO, S;STROSBERG, AD
通讯作者：
STROSBERG, AD
影响因子：
10.5
作者：
Fernández, AM;Kim, JK;Le Roith, D
通讯作者：
Le Roith, D
影响因子：
5
作者：
Coughlin, SS;Calle, EE;Thun, MJ
通讯作者：
Thun, MJ
DOI：
10.1073/pnas.91.12.5677
发表时间：
1994-06-07
影响因子：
11.1
作者：
FEVE, B;ELHADRI, K;PAIRAULT, J
通讯作者：
PAIRAULT, J
影响因子：
--
作者：
Gouon-Evans, V;Pollard, JW
通讯作者：
Pollard, JW