Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity.
Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity.
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DOI：
10.1530/erc-11-0213
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发表时间：
2012-02
影响因子：
3.9
通讯作者：
Leticia M. Nogueira;Sarah M. Dunlap;Nikki A. Ford;S. Hursting
中科院分区：
文献类型：
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作者：
Leticia M. Nogueira;Sarah M. Dunlap;Nikki A. Ford;S. Hursting
肥胖是绝经后乳腺癌的一个确定的风险和进展因素。减少热量摄入和/或增加能量消耗的干预措施有益地影响正常体重人类和动物模型中的肿瘤进展。然而，尽管肥胖症的全球患病率越来越高，但这些能量平衡调节干预措施的效果和潜在机制在肥胖个体中的特征很差。本研究的目的是更好地描述绝经后肥胖背景下能量平衡与乳腺癌进展之间联系的机制。我们比较了热量限制（CR），跑步机运动（EX）和哺乳动物雷帕霉素靶点（mTOR抑制剂）治疗对肥胖小鼠身体成分，血清生物标志物，细胞信号传导和乳腺肿瘤生长的影响。对切除卵巢的C57 BL/6小鼠施用饮食诱导的肥胖方案8周，然后随机分为三个治疗组：对照组（随意喂食半纯化饮食，维持肥胖状态）; 30%CR（相对于对照的等营养素，除了碳水化合物卡路里减少30%）;和EX（随意喂食对照饮食加跑步机运动）。在第12周，向小鼠植入同基因MMTV-Wnt-1乳腺肿瘤细胞。雷帕霉素治疗（每48小时5 mg/kg）在第14周开始。在第18周切除肿瘤。与对照相比，CR和雷帕霉素（但不是EX）显著降低最终肿瘤重量。在随访分析中，mTOR的组成性激活消除了CR对Wnt-1乳腺肿瘤生长的抑制作用。我们得出结论，mTOR抑制可能是一种药理学策略，以模拟CR的抗癌作用，并打破肥胖-乳腺癌进展的联系。
Obesity is an established risk and progression factor for postmenopausal breast cancer. Interventions to decrease caloric intake and/or increase energy expenditure beneficially impact tumor progression in normoweight humans and animal models. However, despite the increasingly high global prevalence of obesity, the effects and underlying mechanisms of these energy balance modulating interventions are poorly characterized in obese individuals. The goal of this study was to better characterize the mechanism(s) responsible for the link between energy balance and breast cancer progression in the postmenopausal obesity context. We compared the effects of calorie restriction (CR), treadmill exercise (EX), and mammalian target of rapamycin (mTOR inhibitor) treatment on body composition, serum biomarkers, cellular signaling, and mammary tumor growth in obese mice. Ovariectomized C57BL/6 mice were administered a diet-induced obesity regimen for 8 weeks, then randomized into three treatment groups: control (semipurified diet fed ad libitum, maintained the obese state); 30% CR (isonutrient relative to control except 30% reduction in carbohydrate calories); and EX (control diet fed ad libitum plus treadmill exercise). Mice were implanted with syngeneic MMTV-Wnt-1 mammary tumor cells at week 12. Rapamycin treatment (5 mg/kg every 48 h) started at week 14. Tumors were excised at week 18. CR and rapamycin (but not EX) significantly reduced final tumor weight compared to control. In follow-up analysis, constitutive activation of mTOR ablated the inhibitory effects of CR on Wnt-1 mammary tumor growth. We conclude that mTOR inhibition may be a pharmacologic strategy to mimic the anticancer effects of CR and break the obesity-breast cancer progression link.