Metformin for Reduction of Obesity Associated Breast Cancer Risk

二甲双胍可降低肥胖相关乳腺癌风险

• 批准号: 9108151
• 负责人: H-H. Sherry CHOW
• 金额: $ 62.86万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-11 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108151
• 关键词: 5' -AMP-activated protein kinase; Adult; Adverse effects; Animals; Antidiabetic Drugs; Biochemical; Blood Glucose; Body Weight; Breast; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Cancer Treatment; Case-Control Studies; Cell Proliferation; Chemopreventive Agent; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Detection; Development; Diabetes Mellitus; Disease; Evaluation; Fatty acid glycerol esters; General Population; Gonadal Steroid Hormones; Health; High Prevalence; Hormones; Incidence; Induction of Apoptosis; Insulin; Insulin Resistance; Intervention; Lead; Life Style; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary gland; Measures; Mediating; Menopause; Metabolic; Metabolic Diseases; Metabolic syndrome; Metformin; Obesity; Overweight; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Plasma; Populations at Risk; Postmenopause; Premenopause; Prevention; Preventive; Public Health; Randomized; Research; Risk; Risk Factors; Risk Reduction; Signal Pathway; Somatomedins; Systems Biology; Tissues; Water; Weight; Weight Gain; Woman; Work; adipokines; breast density; cancer risk; cancer therapy; cytokine; diabetic; double-blind placebo controlled trial; experience; high risk; malignant breast neoplasm; metabolic phenotype; metabolome; metabolomics; nipple aspirate fluid; novel; prospective; research clinical testing; study population; treatment group; tumor; uptake

DESCRIPTION (provided by applicant): High adiposity is a major risk factor for a number of diseases, including postmenopausal breast cancer. It has been suggested that adulthood weight gain is more strongly associated with postmenopausal breast cancer than current weight. Prospective cohort studies suggested that approximately 20% of the postmenopausal breast cancer cases are attributable to adulthood weight gain. The increased postmenopausal breast cancer risk in women with high adiposity is likely to be attributed to multiple metabolic disturbances. Metformin, a widely used antidiabetic drug, exerts favorable effects on multiple metabolic disturbances which may lead to reduction of breast cancer risk in women with high adiposity. In addition, metformin may work directly in mammary tissue through the activation of the AMP- activated protein kinase (AMPK) signaling pathway, leading to an antiprolierative effect and induction of apoptosis. Recent case control and cohort studies found that treatment with metformin appears to substantially reduce the risk for development of cancer in diabetics, including breast cancer. There are a large number of ongoing clinical trials of metformin in breast cancer patients. However, the concurrent or prior breast cancer treatments in these studies hinder the evaluation of metformin as a single agent for breast cancer prevention in at risk healthy women. We propose to conduct a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have experienced moderate to significant adulthood weight gain, have high breast density and are insulin resistant. This study population is at increased risk for postmenopausal breast cancer and has a high prevalence of metabolic disturbances associated with breast cancer risk. The overall hypothesis is that metformin intervention can modulate risk features of the breast and metabolic disturbances associated with breast cancer risk in women with high adiposity. The specific aims for this project are 1) to determine the effect of metformin intervention on breast density, 2) to determine the effect of metformin intervention on metabolic disturbances and body weight/composition, and 3) to explore the application of metabolomics as a systems biology approach to assess the chemopreventive mechanisms of metformin. Our proposed study represents the initial steps in clinical evaluation of metformin for modulation of breast cancer rik in a population at risk for multiple diseases. Findings from this study will have wide public healt impact because of the growing overweight and obese populations. With its demonstrated effect in reducing the incidence of diabetes in high risk adults, metformin would have a high level of acceptance and uptake in at risk women with high adiposity if it has also been shown to exert favorable activities in breast cancer risk reduction. Considering the challenges in maintaining a healthy life style by the majority of general public and the pleiotropic activities of metformin fo multiple metabolic disorders, metformin could be developed as an integrated pharmacological approach for at risk women with high adiposity for prevention of multiple diseases.

描述（由申请人提供）：高肥胖是多种疾病（包括绝经后乳腺癌）的主要危险因素。已经提出，成年体重增加与绝经后乳腺癌更密切相关，而不是目前的体重。前瞻性队列研究表明，绝经后乳腺癌病例中约有20％归因于成年体重的增加。高脂肪症女性的绝经后乳腺癌风险增加可能归因于多种代谢障碍。 二甲双胍是一种广泛使用的抗糖尿病药物，对多种代谢性疾病产生了有利的影响，这可能导致脂肪高度高的女性乳腺癌风险降低。此外，通过激活AMP活化蛋白激酶（AMPK）信号通路，二甲双胍可以直接在乳腺组织中起作用，从而导致抗脂肪性效应和诱导凋亡。最近的病例控制和队列研究发现，用二甲双胍治疗似乎大大降低了包括乳腺癌在内的糖尿病患者的癌症发展风险。在乳腺癌患者中，二甲双胍正在进行大量临床试验。但是，在这些研究中，并发或先前的乳腺癌治疗阻碍了二甲双胍作为预防健康女性乳腺癌的单一药物的评估。 我们建议在超重/肥胖的绝经前妇女中进行II期随机，双盲，安慰剂对照试验，这些试验经历了中度至显着的成年体重增加，具有较高的乳腺癌密度并且具有胰岛素耐药性。这项研究人群的绝经后乳腺癌风险增加，并且与乳腺癌风险有关的代谢障碍患病率很高。总体假设是，二甲双胍干预可以调节乳腺癌高脂肪的乳腺癌风险与乳腺癌风险相关的代谢障碍的风险特征。该项目的具体目的是1）确定二甲双胍干预对乳腺密度的影响，2）确定二甲双胍干预对代谢障碍和体重/组成的影响，以及3）探索代谢组学作为一种系统生物学方法的应用，以评估化学抗性机制。 我们提出的研究代表了二甲双胍调节乳腺癌RIK的临床评估的初始步骤，该人群患有多种疾病的风险。由于超重和肥胖的人群的日益增长，这项研究的发现将产生广泛的公共愈合影响。由于其在降低高风险成年人中糖尿病的发生率方面的作用，二甲双胍如果还显示出在乳腺癌风险降低中发挥有利的活动，那么耐肥胖的妇女的接受程度很高。考虑到大多数普通公众维持健康生活方式的挑战以及多种代谢性疾病的二甲双胍的多效活动，可以作为一种综合药理方法来开发，以预防多种疾病的崇拜性妇女的综合药理方法。