Prevention of mammary tumors by metformin in comparison to calorie restriction

与热量限制相比，二甲双胍预防乳腺肿瘤

基本信息

批准号：
8706080
负责人：
Margot P Cleary
金额：
$ 30.69万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8706080
关键词：
Adenocarcinoma Adenosine Monophosphate Adverse effects Age Animal Model Appearance Biological Assay Body Weight Body Weight decreased Body mass index Breast Cancer Model Breast Cancer Prevention Breast Epithelial Cells Caloric Restriction Calories Categories Cell Proliferation Censuses Cessation of life Clinical Trials Data Detection Development Diet Eating Epithelial Cell Proliferation Exhibits FDA approved Fatty acid glycerol esters Female Glucose Growth Factor Height High Risk Woman Hormone Responsive Human Incidence Insulin Insulin-Like Growth Factor I Intervention Intervention Studies Lead Life Maintenance Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Measurement Mediating Metformin Modeling Mouse Mammary Tumor Virus Mus Non-Insulin-Dependent Diabetes Mellitus Normal Range Obesity Outcome Outcome Study Overweight Pathway interactions Perimenopause Phosphotransferases Play Postmenopause Pre-Clinical Model Prevention Prevention strategy Preventive Preventive Intervention Process Proteins Protocols documentation Public Health Regimen Reporting Resistance Risk Risk Factors Rodent Rodent Model Role Sampling Serum Sexual Development Specific qualifier value Tamoxifen Time Tissues Transgenic Mice Transgenic Organisms Treatment Efficacy Tumor Burden Tumor Pathology Water consumption Weight Weight Gain Woman base breast cancer diagnosis chemical carcinogen clinically relevant design diabetic feeding high risk in vivo interest malignant breast neoplasm mimetics mouse model non-compliance normal aging pre-clinical preclinical study prevent primary outcome rapid growth tumor

项目摘要

DESCRIPTION (provided by applicant): Obesity is a risk factor for postmenopausal breast cancer. However, there are few studies that have evaluated the impact of prevention strategies such as calorie restriction in preclinical obesity protocols. In rodents it is easy to implement calorie restriction but in humans weight loss regimens have poor outcomes including noncompliance and weight regain leading to interest in calorie restriction mimetics including metformin. Here, we will directly compare the impact of calorie restriction to metformin treatment in a clinically relevant model of hormone responsive breast cancer. Our hypothesis is that metformin will reduce mammary tumor incidence, extend latency and reduce tumor burden to a similar degree as moderate calorie restriction. Specific Aim 1: To determine effects of metformin and calorie restriction on the development of mammary tumors, i.e., incidence, latency, tumor burden and tumor pathology in relationship to body weight. Specific Aim 2: To compare the impact of metformin and calorie restriction on longitudinal measurement of serum factors involved in mammary tumor development, i.e., insulin, glucose and IGF-I. Specific Aim 3: To assess the impact of metformin and calorie restriction on mammary epithelial cell proliferation in vivo in relationship to mammary tissue expression levels of proteins associated with proliferation and the AMPK pathway. We will use female MMTV-TGF-1/C57BL6 mice which develop mammary tumors in their second year. Mice will be fed a 33% fat diet or maintained on a low-fat normal mouse diet from 10 weeks of age (Normal Weight). Mice fed the high-fat diet will be stratified by body weight gain at 30 weeks of age into three groups as previously reported (Int.J.Obesity 28:956,2004). The heaviest mice will be designated as Obesity-Prone, the middle group as Overweight and the lightest group, Obesity-Resistant, are mice which remain in the weight range of Normal-Weight mice. This relationship is similar to what occurs in humans, i.e., diets are similar but body weights vary considerably. At 30 weeks of age mice in each body weight group will be fed Ad libitum, 25% calorie restricted or treated with metformin (100 or 200 mg/kg body weight/day) and followed until 90 weeks of age. Food intake, water consumption and body weights will be determined. Serum samples will be obtained prior to interventions and at specified time points to determine if IGF-I, insulin and/or glucose play a role in tumor development/prevention. Mammary tumor incidence, latency and tumor burden in relation to body weight and intervention will be the primary outcome. In vivo mammary cell proliferation prior to interventions and at the end of the study will be determined. Tumors and mammary tissue will be assayed for proteins associated with the AMPK pathway which is considered to be important in the actions of both calorie restriction and metformin treatment. The information obtained will provide evidence of the impact of metformin treatment and calorie restriction on mammary tumor development in relation to body weight status and will hopefully lead to human trials of obese women at high risk for breast cancer.

描述（由申请人提供）：肥胖是绝经后乳腺癌的危险因素。然而，很少有研究评估临床前肥胖方案中热量限制等预防策略的影响。在啮齿类动物中，很容易实施热量限制，但在人类中，减肥方案效果不佳，包括不依从和体重反弹，导致人们对包括二甲双胍在内的热量限制模拟物产生兴趣。在这里，我们将在激素反应性乳腺癌的临床相关模型中直接比较热量限制对二甲双胍治疗的影响。我们的假设是，二甲双胍将降低乳腺肿瘤的发病率、延长潜伏期并减轻肿瘤负担，其程度与适度热量限制相似。具体目标 1：确定二甲双胍和热量限制对乳腺肿瘤发展的影响，即发病率、潜伏期、肿瘤负荷和肿瘤病理学与体重的关系。具体目标 2：比较二甲双胍和热量限制对乳腺肿瘤发展涉及的血清因子（即胰岛素、葡萄糖和 IGF-I）纵向测量的影响。具体目标 3：评估二甲双胍和热量限制对体内乳腺上皮细胞增殖的影响，以及与增殖和 AMPK 途径相关的乳腺组织蛋白表达水平的关系。我们将使用在第二年出现乳腺肿瘤的雌性 MMTV-TGF-1/C57BL6 小鼠。从 10 周龄（正常体重）开始，小鼠将被喂食 33% 脂肪饮食或维持低脂正常小鼠饮食。如之前报道的(Int.J.Obesity 28：956，2004)，将喂食高脂肪饮食的小鼠在30周龄时根据体重增加分为三组。最重的小鼠将被指定为易肥胖组，中间组为超重组，最轻组为抗肥胖组，这些小鼠的体重仍处于正常体重小鼠的范围内。这种关系与人类的关系类似，即饮食相似，但体重差异很大。在30周龄时，每个体重组中的小鼠将被随意喂养，25%热量限制或用二甲双胍（100或200mg/kg体重/天）治疗，并随访直至90周龄。将确定食物摄入量、水消耗量和体重。将在干预之前和特定时间点获取血清样本，以确定 IGF-I、胰岛素和/或葡萄糖是否在肿瘤发展/预防中发挥作用。乳腺肿瘤的发病率、潜伏期以及与体重和干预相关的肿瘤负荷将是主要结果。将确定干预前和研究结束时的体内乳腺细胞增殖。将检测肿瘤和乳腺组织中与 AMPK 途径相关的蛋白质，该途径被认为在热量限制和二甲双胍治疗的作用中很重要。获得的信息将提供二甲双胍治疗和热量限制对与体重状况相关的乳腺肿瘤发展的影响的证据，并有望导致对乳腺癌高危肥胖女性进行人体试验。