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Obesity, Metabolism and Breast Cancer Metastasis

肥胖、新陈代谢和乳腺癌转移

基本信息

批准号：
10079476
负责人：
Stephen D Hursting
金额：
$ 45.88万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10079476
关键词：
Address Adoption Animal Model Breast Cancer Cell Breast Cancer Risk Factor Breast Epithelial Cells Breast cancer metastasis Cell Culture Techniques Cell Proliferation Cell Survival Cells Cessation of life Chemicals Citric Acid Cycle Development Disease Distal Energy Metabolism Environment Enzymes Extracellular Matrix Fatty Acids Future Genetic Glucose Intervention Leptin Life Expectancy Life Style Light Link Lung Malignant Neoplasms Metabolic Metabolism Metastatic Neoplasm to the Lung Metastatic to Modeling Molecular Neoplasm Metastasis Nutrient Obesity Obesity Epidemic Organ Overweight Oxaloacetates Oxygen Patients Positioning Attribute Primary Neoplasm Process Pyruvate Pyruvate Carboxylase Quality of life Recommendation Recurrence Regulation Reporter Research Risk Role Site Stable Isotope Labeling Stress System Testing Tissues Up-Regulation Woman Work adipokines base breast cancer progression breast tumorigenesis cell type evidence based guidelines fatty acid metabolism flexibility genetic manipulation in vivo Model inhibitor/antagonist leptin receptor lipidomics malignant breast neoplasm mammary metabolomics migration mortality risk mouse model neoplastic cell obesity prevention overexpression prevent receptor expression targeted treatment tumor tumor metabolism

项目摘要

PROJECT SUMMARY While significant evidence has demonstrated that obesity increases the risk of metastasis, the molecular mechanisms by which obesity contributes to the metastatic progression of breast cancer are unclear. Further, recent research in cancer development and progression has highlighted the role of metabolic reprogramming, which results in an increased supply of the cellular building blocks necessary for the increased cell proliferation and in adaptations required for cell survival in changing nutrient- and oxygen-containing environments. Research from our team and others demonstrates that the metabolic enzyme, pyruvate carboxylase, is upregulated during obesity and that this upregulation correlates strongly with breast cancer progression. Additional studies suggest that leptin, an adipokine whose expression is increased during obesity and whose receptor's expression is enhanced in metastatic cells, drives pyruvate carboxylase expression in breast cancer cells. Importantly, recent studies demonstrate that genetic depletion of pyruvate carboxylase drastically inhibits breast cancer metastasis in several syngeneic mouse models. Despite the supporting evidence that pyruvate carboxylase contributes to breast cancer metastasis under obese conditions, the mechanisms by which this enzyme exerts this effect remain poorly understood. In the proposed studies, the research team will evaluate the mechanistic basis by which pyruvate carboxylase regulates obesity-driven breast cancer metastasis. They will test the hypotheses that leptin increases pyruvate carboxylase expression in mammary tissue during obese states, and that pyruvate carboxylase is critical for both migration and survival of extracellular matrix detachment, providing metabolic flexibility (e.g., glucose utilization and fatty acid metabolism) during metastasis. These hypotheses will be tested through completion of the following aims: 1) define the mechanisms of PC expression during metastasis; 2) elucidate the metabolic mechanisms by which PC promotes metastasis; and 3) establish the mechanisms by which leptin-regulated PC expression contributes to obesity-driven metastasis. Completion of these studies will result in valuable mechanistic information that could guide future development of evidence-based recommendations for those who are overweight and obese and that will help reduce breast cancer metastasis.

项目概要虽然重要证据表明肥胖会增加转移风险，但分子生物学肥胖导致乳腺癌转移进展的机制尚不清楚。更远，最近对癌症发生和进展的研究强调了代谢重编程的作用，这导致增加细胞增殖所需的细胞构建块的供应增加以及细胞在不断变化的营养和含氧环境中生存所需的适应。我们团队和其他人的研究表明，代谢酶丙酮酸羧化酶是肥胖期间上调，并且这种上调与乳腺癌进展密切相关。其他研究表明，瘦素是一种脂肪因子，其表达在肥胖期间增加，并且其转移细胞中受体的表达增强，驱动乳腺癌中丙酮酸羧化酶的表达细胞。重要的是，最近的研究表明，丙酮酸羧化酶的基因缺失会极大地抑制几种同基因小鼠模型中的乳腺癌转移。尽管有支持证据表明丙酮酸羧化酶在肥胖条件下促进乳腺癌转移，其机制酶发挥这种作用仍知之甚少。在拟议的研究中，研究小组将评估丙酮酸羧化酶调节肥胖驱动的乳腺癌转移的机制基础。他们将检验瘦素在乳腺组织中增加丙酮酸羧化酶表达的假设肥胖状态，丙酮酸羧化酶对于细胞外基质的迁移和存活至关重要分离，提供代谢灵活性（例如，葡萄糖利用和脂肪酸代谢）转移。这些假设将通过完成以下目标进行检验：1）定义转移过程中PC表达的机制； 2）阐明PC的代谢机制促进转移； 3) 建立瘦素调节 PC 表达的机制肥胖驱动的转移。完成这些研究将产生有价值的机制信息，可以指导未来为超重和肥胖者制定基于证据的建议，这将有助于减少乳腺癌转移。