Targeting the IKKβ/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-related breast cancer.
Targeting the IKKβ/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-related breast cancer.
复制标题
DOI：
10.1158/1535-7163.mct-12-0180
复制
发表时间：
2012-10
影响因子：
5.7
通讯作者：
Hung MC
中科院分区：
文献类型：
--
作者：
Chen CT;Du Y;Yamaguchi H;Hsu JM;Kuo HP;Hortobagyi GN;Hung MC
临床相关性研究清楚地表明，肥胖与乳腺癌风险和患者生存率相关。虽然已经提出了几个潜在的机制联系肥胖和癌症，肥胖介导的乳腺肿瘤发生的详细分子机制尚未得到严格的评价。在这项研究中，我们评估了肥胖对乳腺肿瘤发生和发展的影响，使用遗传和饮食诱导的肥胖小鼠乳腺肿瘤异种移植物和小鼠乳腺肿瘤virusneu转基因小鼠，喂养高脂肪饮食。我们发现，肥胖促进乳腺肿瘤的生长和发展，在这些动物模型。此外，肥胖小鼠乳腺肿瘤中TNFα、VEGF、IKKβ和mTOR的表达上调，提示肥胖小鼠肿瘤中TNFα激活了IKKβ/ mTOR/VEGF信号通路。更重要的是，靶向该通路成员的抑制剂（雷帕霉素、贝伐单抗和阿司匹林）在肥胖小鼠中比在非肥胖小鼠中更有效地抑制肿瘤发生并延长生存期。在这里，我们不仅确定了一种有助于肥胖小鼠乳腺肿瘤发生的特定信号通路，而且还确定了治疗肥胖介导的乳腺癌的策略。
Clinical correlation studies have clearly shown that obesity is associated with breast cancer risk and patient survival. Although several potential mechanisms linking obesity and cancers have been proposed, the detailed molecular mechanism of obesity-mediated breast tumorigenesis has not yet been critically evaluated. In this study, we evaluated the effects of obesity on mammary tumor initiation and progression using mice with genetic and diet-induced obesity bearing mammary tumor xenografts and mouse mammary tumor virusneu transgenic mice that were fed a high-fat diet. We show that obesity promoted mammary tumor growth and development in these animal models. Moreover, the expressions of TNFα, VEGF, IKKβ, and mTOR are upregulated in mammary tumors of obese mice, suggesting that the IKKβ/ mTOR/VEGF signaling pathway is activated by TNFα in the tumors of obese mice. More importantly, inhibitors (rapamycin, bevacizumab, and aspirin) that target members of the pathway suppressed tumorigenesis and prolonged survival more effectively in obese mice than in nonobese mice. Here, we not only identified a specific signaling pathway that contributes to mammary tumorigenesis in obese mice but also a strategy for treating obesity-mediated breast cancer.