Time-restricted feeding and breast cancer

限时喂养与乳腺癌

• 批准号: 10462993
• 负责人: NICHOLAS J WEBSTER
• 金额: $ 33.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462993
• 关键词: Age; Age-Years; Aging; Automobile Driving; Autophagocytosis; Behavior Therapy; Body Weight decreased; Breast Cancer Model; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Cancer therapy; Cancer Model; Carcinogens; Cell Proliferation; Central obesity; Circadian Rhythms; Clinical Research; Colon Carcinoma; Cues; Data; Diagnosis; Dietary Intervention; Disease-Free Survival; Distant Metastasis; Dose; Eating; Elements; Energy Intake; Epidemiology; Estrogen receptor positive; Estrogens; Exposure to; Fasting; Goals; Growth; Health Benefit; High Fat Diet; Hormonal; Human; Hyperinsulinism; Incidence; Inflammation; Insulin; Insulin Receptor; Insulin Resistance; Intake; Intervention; Lead; Link; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Mammary Neoplasms; Mediating; Metabolic; Mus; Neoplasm Metastasis; Nutrient; Obesity; Obesity Epidemic; Omega-3 Fatty Acids; Oncogenes; Outcome; Ovarian; Patients; Population; Postmenopause; Premenopause; Prevention therapy; Protein Inhibition; Receptor Signaling; Recurrence; Risk; Rodent; Role; Series; Signal Pathway; Signal Transduction; Testing; Time; Time-restricted feeding; Tissues; Translations; Woman; animal data; antitumor effect; blood glucose regulation; cancer cell; cancer initiation; cancer risk; cancer survival; cancer therapy; chemotherapy; circadian pacemaker; combat; dietary; epidemiologic data; epidemiology study; experimental study; feeding; genetic approach; hormone therapy; improved; in vivo; inflammatory breast cancer; insulin signaling; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; obese person; orthotopic breast cancer; patient derived xenograft model; pre-clinical; preclinical study; prevent; reduced food intake; response; time use; translational approach; translational potential; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression; weight loss intervention

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.

有大量证据表明，肥胖会增加至少13种癌症的风险。的 乳腺癌、结肠癌和肝癌的发病率在肥胖人群中都有所增加， 肥胖与乳腺癌之间的联系的证据尤其有力。八分之一的女性将被诊断为 患乳腺癌的几率。女性乳腺癌发病率增加约10倍 与50岁或更年轻的人相比，60岁以上的人。乳腺癌风险的增加与 肥胖症的增加。事实上，肥胖会增加绝经前妇女患三阴性乳腺癌的风险 和绝经后妇女的雌激素受体阳性乳腺癌。一种罕见的炎症性乳腺炎 在两组中癌症都显著增加（高达5倍）。更重要的是，肥胖缩短了 绝经前和绝经后妇女的生存率。乳腺癌患者的死亡率主要是由远处转移引起的。 转移诊断时肥胖与远处转移和死亡率的风险增加有关。 对啮齿类动物的研究证实了这些关系，表明饮食引起的肥胖和高脂肪 饮食导致癌基因和致癌物诱发的乳腺癌的发病率和肿瘤生长增加。 尽管有这些相关的证据，肥胖导致乳腺癌风险的机制仍然很差 明白一种可能性是肥胖导致肝脏胰岛素抵抗和代偿性升高 来控制血糖水平与此同时，其他组织，包括肿瘤， 胰岛素抵抗，因此暴露于增加的胰岛素信号。事实上，我们已经证明， 通过用omega-3脂肪酸治疗抵抗降低小鼠乳腺癌的生长。我们还表明， 限时喂养（TRF）与无限制的高脂肪饮食喂养相比， 持续的肥胖和相同的热量摄入。此外，我们发现TRF抑制肥胖驱动的乳腺癌， 肿瘤生长和纠正肿瘤昼夜节律，TRF对肿瘤生长的影响是介导的， 通过降低胰岛素水平。一些重要的问题仍然没有答案。首先，胰岛素如何驱动 肿瘤生长？它是对肿瘤细胞的直接影响，还是对微环境的影响？第二，纠正 TRF在肿瘤细胞中的昼夜节律有助于减少肿瘤生长？第三，营养素如何 和胰岛素会影响肿瘤的生物钟吗由于肥胖、胰岛素抵抗和乳腺癌之间的联系， 绝经前和绝经后妇女的癌症，以及限时喂养的转化潜力，我们将 研究删除胰岛素受体、mTORC 1信号传导或生物钟成分的影响 在肿瘤细胞中检测这些信号的丢失是否改变了体内肿瘤的生长和对TRF的反应。我们将 也测试TRF是否增强化学疗法以抑制肿瘤生长。收集与TRF有关的证据 临床研究支持我们建议的翻译相关性。这些转化的机械发现 研究将对乳腺癌的预防和治疗产生影响。