Impact of hypoxia on lipid metabolism in obesity-driven breast cancer progression

缺氧对肥胖驱动的乳腺癌进展中脂质代谢的影响

• 批准号: 10604919
• 负责人: Stephen D Hursting
• 金额: $ 65.54万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-28 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604919
• 关键词: Address; Biological Assay; Breast Cancer Patient; Breast cancer metastasis; Carnitine Palmitoyltransferase I; Cell Survival; Cells; Cessation of life; Chronic; Cytoprotection; Data; Development; Disease Progression; Energy Supply; Environment; Enzymes; Equilibrium; Exposure to; Fatty Acids; Fatty-acid synthase; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Hypoxia; IL-6 inhibitor; In Vitro; Inflammation; Inflammatory; Interleukin-6; Laboratories; Light; Lipids; Malignant Neoplasms; Mediating; Memory; Metabolic; Metastatic breast cancer; Mitochondria; Modeling; Molecular; Neoplasm Metastasis; Obesity; Obesity Epidemic; Oxidative Stress; Oxygen; Patient-Focused Outcomes; Patients; Positioning Attribute; Primary Lesion; Primary Neoplasm; Production; Prognosis; Proteins; Publishing; Pyruvate Carboxylase; Recommendation; Reporter; Research; Risk; Role; STAT3 gene; Signal Transduction; Site; Stable Isotope Labeling; System; Testing; Up-Regulation; Work; breast cancer progression; cancer cell; cytokine; diet-induced obesity; fatty acid oxidation; improved; in vivo; lipid metabolism; malignant breast neoplasm; mortality risk; mouse model; neoplastic cell; novel; obesity prevention; pharmacologic; tumor microenvironment

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. Furthermore, recent research in cancer development and progression has highlighted the role of hypoxia and dysregulated lipid metabolism. Research from our team and others demonstrate that lipid accumulation, which is associated with reduced patient outcomes, is greater in metastases compared to primary tumors. Furthermore, hypoxia, which is increased in obesity in the primary tumor, leads to sustained increase in the expression of specific genes after reoxygenation, a hypoxic memory. Our results demonstrate that hypoxic memory results in the expression of fatty acid synthase (FASN), which is the rate-limiting step in fatty acid synthesis, and pyruvate carboxylase (PC), which we have shown provides oxidative stress protection. In addition, the inflammatory cytokine interleukin-6 (IL-6), which is elevated in obesity, enhances the expression of CPT1A, the rate-limiting step in fatty acid oxidation (FAO) to supply energy. Our preliminary data show that the expression of these three proteins and their functional consequences of increased fatty acid synthesis and FAO are elevated in metastases compared to primary tumors. Thus, our preliminary results suggest that hypoxia may set the stage for dysfunctional lipid metabolism, where increased lipid synthesis and utilization occur concurrently with a balance towards lipid accumulation. However, the impact of dysfunctional lipid metabolism in obesity-driven metastasis is unknown despite the supporting evidence that hypoxia and IL-6 are enhanced in obesity. In the proposed studies, the research team will utilize multiple mouse models of obesity and metastatic breast cancer to evaluate the mechanistic basis by which hypoxic memory and IL-6 interact to stimulate obesity-driven breast cancer metastasis. They will test the hypothesis that obesity-associated increases in hypoxic memory and proinflammatory IL-6 signaling work in tandem to increase FA accumulation (FASN), FAO (CPT1), and cell survival (PC) to enhance metastases. These hypotheses will be tested through the completion of the following two aims: 1) determine the impact of hypoxic memory on lipid accumulation in obesity-driven metastasis, and 2) establish the interaction of hypoxic memory with chronic inflammation in obesity-driven metastasis. These studies will provide foundational evidence for developing targeted strategies to mitigate obesity-driven metastatic breast cancer.

项目摘要 尽管大量证据表明肥胖会增加转移的风险，但分子 肥胖有助于乳腺癌的转移性进展的机制尚不清楚。 此外，癌症发展和进展方面的最新研究强调了缺氧和 脂质代谢失调。我们团队和其他人的研究表明，脂质积累 与降低的患者结局有关，与原发性肿瘤相比，转移量更大。 此外，原发性肿瘤中肥胖的缺氧导致持续增加 重氧后特定基因的表达，一种低氧记忆。我们的结果表明缺氧 记忆会导致脂肪酸合酶（FASN）的表达，这是脂肪酸的限速步骤 我们已经显示的合成和丙酮酸羧化酶（PC）提供了氧化应激保护。在 此外，肥胖症中升高的炎性细胞因子白细胞素6（IL-6）增强了表达 CPT1A，脂肪酸氧化（FAO）的限速步骤供应能量。我们的初步数据表明 这三种蛋白质的表达及其功能后果增加了脂肪酸合成和 与原发性肿瘤相比，粮农组织在转移中升高。因此，我们的初步结果表明 缺氧可能为功能失调的脂质代谢奠定了阶段，脂质合成和利用率增加 同时发生，朝着脂质积聚的平衡。但是，功能障碍脂质的影响 尽管有支持证据表明缺氧和IL-6是肥胖驱动转移中的代谢是未知的 肥胖增强。在拟议的研究中，研究小组将利用多种肥胖的鼠标模型 和转移性乳腺癌以评估低氧记忆和IL-6相互作用的机理基础 刺激肥胖驱动的乳腺癌转移。他们将检验与肥胖相关的假设 在同时增加缺氧记忆和促炎性IL-6信号转导工作以增加FA的积累 （FASN），粮农组织（CPT1）和细胞存活（PC），以增强转移。这些假设将通过 以下两个目的的完成：1）确定缺氧记忆对脂质积累的影响 肥胖驱动的转移和2）建立低氧记忆与慢性炎症的相互作用 肥胖驱动的转移。这些研究将为制定目标策略提供基本证据 减轻肥胖驱动的转移性乳腺癌。