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

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

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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，肥胖症赋予了至少13种癌症的风险增加。这肥胖种群中的乳腺癌，结肠癌和肝癌的发病率均增加，并且流行病学肥胖 - 胸癌连接的证据特别有力。将诊断出八分之一的女人一生中乳腺癌。女性的乳腺癌发病率增加了约10倍在60岁以上，而50岁或以上。乳腺癌风险的增加与肥胖的增加。实际上，肥胖增加了绝经前女性三阴性乳腺癌的风险绝经后妇女的雌激素受体阳性乳腺癌。炎症性乳房的稀有形式两组的癌症均大幅增加（最多5倍）。更重要的是，肥胖可以缩短无病绝经前和绝经后妇女的生存。乳腺癌的患者死亡率主要由远处引起转移。诊断时肥胖与远处转移和死亡率的风险增加有关。啮齿动物的研究证实了这些关系，表明饮食引起的肥胖症和高脂饮食会导致癌基因和致癌物诱导的乳腺癌的发病率和生长增加。尽管有相关的证据，但肥胖引起的乳腺癌风险的机制仍然很差理解。一种可能性是肥胖症在肝脏中引起胰岛素抵抗和补偿性高程在循环胰岛素中以控制葡萄糖水平。同时，其他组织（包括肿瘤）可能不是胰岛素耐药性，因此暴露于胰岛素信号增加。确实，我们已经证明了减少胰岛素通过用omega-3脂肪酸处理来减少小鼠乳腺癌的生长。我们还表明时间限制的进食（TRF）与高脂饮食的无限制喂养可提高胰岛素抵抗持续的肥胖和同等的热量摄入量。此外，我们表明TRF抑制了肥胖驱动的乳房肿瘤生长和校正的肿瘤昼夜节律，介导了TRF对肿瘤生长的影响通过降低胰岛素水平。许多重要的问题仍未得到解决。首先，胰岛素如何驱动肿瘤生长？它是对肿瘤细胞还是微环境的直接影响？其次，确实对 TRF在肿瘤细胞中的昼夜节律有助于减少肿瘤的生长？第三，营养如何胰岛素吸收了昼夜节律的肿瘤？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时间限制的喂养潜力，我们将研究删除胰岛素受体，MTORC1信号或昼夜节律时钟的成分的效果在肿瘤细胞中测试这些信号的损失是否会改变体内肿瘤的生长和对TRF的反应。我们将还测试TRF是否增强化疗抑制肿瘤生长。与TRF相关的累积证据临床研究支持我们提案的翻译相关性。这些转化，机械性发现研究将影响预防乳腺癌和治疗。