Targeting the IKKβ/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-related breast cancer
Menée sur des modèles murins, cette étude met en évidence le rôle joué par la voie de signalisation IKKβ/mTOR/VEGF dans la formation d'un cancer du sein associé à une obésité
Clinical correlation studies have clearly demonstrated 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 the present 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 virus-neu transgenic mice that were fed a high-fat diet. We demonstrate that obesity promoted mammary tumor growth and development in these animal models. Moreover, the expressions of tumor necrosis factor alpha (TNFα), vascular endothelial growth factor (VEGF), inhibitor of nuclear factor kappa-B beta (IKKβ), and mammalian target of rapamycin (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 non-obese 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.
http://mct.aacrjournals.org/content/early/2012/07/21/1535-7163.MCT-12-0180.abstract 2012