Time-restricted feeding and breast cancer

有大量证据表明，肥胖会增加至少13种癌症的风险。这个 在肥胖人群中，乳腺癌、结肠癌和肝癌的发病率都有所增加，而流行病学 肥胖症和乳腺癌之间的联系的证据尤其有力。每八名女性中就有一名被诊断出 在他们的一生中患有乳腺癌。女性乳腺癌发病率增加约10倍 60岁以上的，而50岁或更年轻的。乳腺癌风险的增加与 肥胖症的增加。的确，肥胖会增加绝经前女性患三阴性乳腺癌的风险。 绝经后妇女雌激素受体阳性乳腺癌。一种罕见的炎症性乳房 在这两组中，癌症的发病率都大幅增加(高达5倍)。更重要的是，肥胖缩短了无病的时间 绝经前和绝经后妇女的存活率。乳腺癌患者的死亡主要是由远处的 转移瘤。确诊时肥胖与远处转移和死亡的风险增加有关。 对啮齿动物的研究已经证实了这些关系，表明饮食导致的肥胖和高脂肪 饮食导致癌基因和致癌物诱导的乳腺癌的发病率和生长增加。 尽管有大量的相关证据，但肥胖导致乳腺癌风险的机制仍然很差。 明白了。一种可能是肥胖导致肝脏胰岛素抵抗和代偿性升高。 在循环胰岛素中控制血糖水平。与此同时，包括肿瘤在内的其他组织可能不会 胰岛素抵抗和胰岛素抵抗暴露于增加的胰岛素信号。事实上，我们已经证明，减少胰岛素 用omega-3脂肪酸治疗的耐药性减少了小鼠乳腺癌的生长。我们还表明， 限时喂养(TRF)与不限制喂食高脂肪饮食相比，尽管 持续肥胖和等量卡路里摄入量。此外，我们还发现TRF可以抑制肥胖引起的乳房 肿瘤生长和纠正的肿瘤昼夜节律，以及TRF对肿瘤生长的影响是中介的 通过降低胰岛素水平。一些重要的问题仍然没有得到回答。首先，胰岛素是如何驱动 肿瘤生长？这是对肿瘤细胞的直接影响，还是对微环境的影响？其次，纠正 TRF在肿瘤细胞中的昼夜节律是否有助于肿瘤生长的减少？第三，营养素是如何 胰岛素会影响肿瘤的生物钟吗？由于肥胖、胰岛素抵抗和乳房之间的联系 绝经前和绝经后妇女的癌症，以及限时喂养的翻译潜力，我们将 研究删除胰岛素受体、mTORC1信号或生物钟成分的影响 以测试这些信号的丢失是否会改变肿瘤在体内的生长和对TRF的反应。我们会 还要测试TRF是否能加强化疗以抑制肿瘤生长。积累与扶轮基金会相关的证据 临床研究支持我们建议的翻译相关性。翻译，机械的发现，从这些 研究将对乳腺癌的预防和治疗产生影响。

There is abundant evidence that obesity confers increased risk for at least 13 forms of cancer. The incidence of breast, colon, and liver cancer are all increased in obese populations, and the epidemiologic evidence for the obesity-breast cancer connection is particularly strong. One in eight women will be diagnosed with breast cancer during their lifetime. Breast cancer incidence increases approximately 10-fold for women over the of age 60, compared to age 50 or younger. This increase in breast cancer risk is associated with an increase in obesity. Indeed, obesity increases the risk of triple-negative breast cancer in premenopausal women and estrogen receptor positive breast cancer in postmenopausal women. A rarer form of inflammatory breast cancer is dramatically increased (up to 5-fold) in both groups. More importantly, obesity shortens disease-free survival in both pre- and postmenopausal women. Patient mortality in breast cancer is primarily caused by distant metastases. Obesity at the time of diagnosis is associated with increased risk of distant metastasis and mortality. Studies in rodents have confirmed these relationships, showing that dietary-induced obesity and high-fat diets lead to increased incidence and growth of tumors in oncogene and carcinogen-induced breast cancers. Despite this body of correlative evidence, the mechanisms of obesity-induced breast cancer risk remain poorly understood. One possibility is that the obesity causes insulin resistance in the liver and compensatory elevation in circulating insulin to control glucose levels. At the same time, other tissues, including tumors, may not be insulin resistant and so are exposed to increased insulin signaling. Indeed, we have shown that reducing insulin resistance by treating with omega-3 fatty acids reduces breast cancer growth in mice. We have also shown that time-restricted feeding (TRF) versus unrestricted feeding of a high-fat diet improves insulin resistance despite sustained obesity and equal caloric intake. Furthermore, we showed that TRF inhibited obesity-driven breast tumor growth and corrected tumor circadian rhythms, and that the TRF impact on tumor growth was mediated by reducing insulin levels. A number of important questions remain unanswered. Firstly, how does insulin drive tumor growth? Is it a direct effect on the tumor cell, or on the microenvironment? Secondly, does correction of the circadian rhythms in the tumor cell by TRF contribute to the reduced tumor growth? Thirdly, how do nutrients and insulin entrain the circadian clock in tumors? Due to the link between obesity, insulin resistance and breast cancer in pre- and postmenopausal women, and the translational potential of time-restricted feeding, we will investigate the effect of deleting the insulin receptor, mTORC1 signaling, or components of the circadian clock in tumor cells to test whether loss of these signals alters tumor growth in vivo and the response to TRF. We will also test whether TRF enhances chemotherapy to inhibit tumor growth. Accumulating evidence from TRF-related clinical studies support the translational relevance of our proposal. Translational, mechanistic findings from these studies will impact on breast cancer prevention and therapy.