Time-Restricted Feeding and Breast Cancer

限时喂养与乳腺癌

• 批准号: 9882965
• 负责人: NICHOLAS J WEBSTER
• 金额: $ 35.46万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9882965
• 关键词: Address; Age; Alleles; Alzheimer' s Disease; Animals; Anti-Inflammatory Agents; Antigens; Backcrossings; Biological Markers; Body Weight decreased; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Risk Factor; Breast Epithelial Cells; Caloric Restriction; Carcinogens; Cell Transplantation; Chemicals; Chronic; Clinical Data; Colon Carcinoma; Consumption; Data; Diagnosis; Diet; Dietary Intervention; Dyslipidemias; Eating; Energy Intake; Epidemiology; Estrogens; Fasting; Fatty Acids; Fatty acid glycerol esters; Female; Growth; High Fat Diet; Histopathology; Hormone replacement therapy; Hormones; Hour; Human; Hunger; Hyperinsulinism; Hypertension; Incidence; Individual; Inflammation; Inflammatory; Injections; Insulin; Insulin Resistance; Intermittent fasting; Intervention; Lead; Link; Longitudinal Studies; Malignant Neoplasms; Malignant neoplasm of liver; Mammary Neoplasms; Mammary gland; Menopause; Meta-Analysis; Metabolic; Metabolic syndrome; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Obese Mice; Obesity; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Oncogenes; Ovarian; Ovariectomy; Ovary; Pharmacology; Phase; Physiological; Polycystic Ovary Syndrome; Polyomavirus; Postmenopause; Premenopause; Protocols documentation; Rag1 Mouse; Resistance; Risk; Rodent; Saturated Fatty Acids; Signal Transduction; Steroids; Stroke; TNF gene; Tail; Testing; Time; Time-restricted feeding; Tissues; Transgenic Organisms; Tumor Necrosis Factor Receptor; Tumor Tissue; Veins; Woman; base; cancer biomarkers; cancer initiation; cancer risk; cytokine; diabetes risk; dietary manipulation; feeding schedule; genetic manipulation; improved; in vivo; insulin sensitivity; insulin sensitizing drugs; male; malignant breast neoplasm; mouse model; neoplastic cell; novel; ovotoxicity; public health relevance; response; time use; transplant model; tumor; tumor growth; tumor initiation

 DESCRIPTION (provided by applicant): There is abundant evidence that obesity confers increased risk for various 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 is incidence increases 10-fold for women age 60 and above, compared to women 50 or younger. The increased breast cancer risk seems to be related to post- menopausal hormone levels, as the increased risk is only seen in women not on hormone replacement therapy. Furthermore the Metabolic Syndrome, which is characterized by obesity, insulin resistance, hypertension, dyslipidemia and elevated risk of diabetes, polycystic ovary syndrome, stroke and Alzheimer's disease, is associated with a higher incidence of more aggressive triple negative breast tumors. The increased risk is accelerated by the decline in ovarian estrogen levels after menopause, as pre-menopausal women are protected from the deleterious metabolic effects of obesity, including chronic tissue inflammation and insulin- resistance. Studies in rodents have confirmed this relationship, 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. Dietary composition is an important factor as diets rich in saturated and omega 6 fatty acids are pro-inflammatory and increase breast cancer risk, but diets rich in omega 3 fatty acids are anti-inflammatory and decrease cancer risk. The clinical data in humans is less clear but meta-analyses of multiple human breast cancer risk studies have suggested that the ratio of pro-inflammatory to anti-inflammatory fatty acids is the critical factor. Although what you eat is important, when you eat i also important. We have found that reducing inflammation and insulin resistance reduces breast cancer growth in mice. We have also found that a time-restricted, high-fat diet improves insulin resistance despite continuing obesity. Due to the link between obesity, insulin resistance and breast cancer risk in post-menopausal women, and the potential that a similar time-restricted, dietary intervention could protect against breast cancer in humans, we will test the dietary intervention on breast cancer growth in mice and investigate the physiological changes that may drive tumor growth in obesity.

 描述（由申请人提供）：有大量证据表明肥胖会增加患各种癌症的风险。肥胖人群中乳腺癌、结肠癌和肝癌的发病率均有所增加，并且肥胖与乳腺癌之间的联系的流行病学证据尤其有力。八分之一的女性在一生中会被诊断出患有乳腺癌。与 50 岁或以下的女性相比，60 岁及以上女性的乳腺癌发病率增加了 10 倍。乳腺癌风险增加似乎与绝经后激素水平有关，因为风险增加仅出现在未接受激素替代治疗的女性中。此外，以肥胖、胰岛素抵抗、高血压、血脂异常以及糖尿病、多囊卵巢综合征、中风和阿尔茨海默病风险升高为特征的代谢综合征与更具侵袭性的三阴性乳腺肿瘤的较高发病率相关。绝经后卵巢雌激素水平下降会加速风险增加，因为绝经前女性可以免受肥胖的有害代谢影响，包括慢性组织炎症和胰岛素抵抗。 对啮齿动物的研究证实了这种关系，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知之甚少。膳食成分是一个重要因素，因为富含饱和脂肪酸和欧米伽 6 脂肪酸的饮食具有促炎作用，会增加患乳腺癌的风险，但富含欧米伽 3 脂肪酸的饮食具有抗炎作用，可降低癌症风险。人类的临床数据尚不清楚，但多项人类乳腺癌风险研究的荟萃分析表明，促炎脂肪酸与抗炎脂肪酸的比率是关键因素。虽然吃什么很重要，但什么时候吃也很重要。 我们发现减少炎症和胰岛素抵抗可以减少小鼠乳腺癌的生长。我们还发现，尽管持续肥胖，但限时的高脂肪饮食仍能改善胰岛素抵抗。由于绝经后女性的肥胖、胰岛素抵抗和乳腺癌风险之间存在联系，并且类似的限时饮食干预可能可以预防人类乳腺癌，因此我们将在小鼠中测试饮食干预对乳腺癌生长的影响，并研究可能促进肥胖中肿瘤生长的生理变化。