Time-restricted feeding and breast cancer

限时喂养与乳腺癌

基本信息

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
项目类别：
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

项目摘要

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。这乳腺癌、结肠癌和肝癌的发病率在肥胖人群中均有所增加，并且流行病学肥胖与乳腺癌之间的联系的证据特别有力。八分之一的女性将被诊断出一生中患有乳腺癌。女性乳腺癌发病率增加约 10 倍 60 岁以上的人与 50 岁或以下的人相比。乳腺癌风险的增加与肥胖增加。事实上，肥胖会增加绝经前女性患三阴性乳腺癌的风险和绝经后女性雌激素受体阳性乳腺癌。一种罕见的炎症性乳房两组的癌症发病率均显着增加（高达 5 倍）。更重要的是，肥胖会缩短无病时间绝经前和绝经后妇女的存活率。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风险增加相关。对啮齿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会导致癌基因和致癌物质诱发的乳腺癌的发病率和生长增加。尽管有大量相关证据，但肥胖诱发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循环胰岛素以控制血糖水平。与此同时，其他组织，包括肿瘤，可能不会胰岛素抵抗，因此会受到胰岛素信号增强的影响。事实上，我们已经证明，减少胰岛素通过使用 omega-3 脂肪酸治疗可降低小鼠乳腺癌的耐药性。我们还表明限时喂养（TRF）与无限制高脂饮食喂养相比，可以改善胰岛素抵抗，尽管持续肥胖和同等热量摄入。此外，我们还发现 TRF 可以抑制肥胖导致的乳房肿瘤生长并纠正肿瘤昼夜节律，并且 TRF 对肿瘤生长的影响是介导的通过降低胰岛素水平。许多重要问题仍未得到解答。一、胰岛素是如何驱动的肿瘤生长？它是对肿瘤细胞还是对微环境的直接影响？其次，是否修正 TRF 调节肿瘤细胞的昼夜节律有助于减少肿瘤生长？三、如何补充营养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存在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、mTORC1 信号传导或生物钟成分的影响在肿瘤细胞中测试这些信号的丢失是否会改变肿瘤体内的生长和对 TRF 的反应。我们将还测试TRF是否增强化疗抑制肿瘤生长。积累TRF相关证据临床研究支持我们建议的转化相关性。来自这些的转化、机制发现研究将对乳腺癌的预防和治疗产生影响。