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

项目摘要 虽然有大量证据表明肥胖会增加转移的风险，但在分子水平上， 肥胖导致乳腺癌转移进展的机制尚不清楚。 此外，最近在癌症发展和进展中的研究已经强调了缺氧和缺氧在癌症中的作用。 脂质代谢失调。我们团队和其他人的研究表明， 与患者预后降低相关，与原发性肿瘤相比，转移性肿瘤的预后更差。 此外，在原发性肿瘤中肥胖时增加的缺氧导致肿瘤组织中的细胞凋亡持续增加。 复氧后特定基因的表达，缺氧记忆。我们的研究结果表明，缺氧 记忆导致脂肪酸合成酶（FATIGATION）的表达，这是脂肪酸合成的限速步骤。 合成和丙酮酸羧化酶（PC），我们已经证明其提供氧化应激保护。在 此外，肥胖时升高的炎性细胞因子白细胞介素-6（IL-6）， CPT 1A是脂肪酸氧化（FAO）提供能量的限速步骤。初步数据显示， 这三种蛋白质的表达及其增加脂肪酸合成的功能后果， 与原发性肿瘤相比，转移瘤中FAO升高。因此，我们的初步结果表明， 缺氧可能会导致脂质代谢功能障碍，脂质合成和利用增加 与脂质积累的平衡同时发生。然而，功能失调的脂质 尽管有支持性证据表明缺氧和IL-6在肥胖驱动的转移中的代谢是未知的， 在肥胖中增强。在拟议的研究中，研究小组将利用多种肥胖小鼠模型 和转移性乳腺癌，以评估缺氧记忆和IL-6相互作用的机制基础， 刺激肥胖导致的乳腺癌转移。他们将检验肥胖相关的 缺氧记忆的增加和促炎性IL-6信号传导协同作用，增加FA积累 （FAP 1）、FAO（CPT 1）和细胞存活（PC）来增强转移。这些假设将通过 完成以下两个目标：1）确定缺氧记忆对脂质积累的影响， 肥胖驱动的转移，和2）建立缺氧记忆与慢性炎症的相互作用， 肥胖导致的转移这些研究将为制定有针对性的战略提供基础证据 来减轻肥胖导致的转移性乳腺癌。

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.