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

项目总结 虽然有重要证据表明肥胖会增加转移的风险，但分子水平 肥胖导致乳腺癌转移进展的机制尚不清楚。 此外，最近对癌症发生和发展的研究强调了缺氧和 脂代谢失调。我们团队和其他人的研究表明，脂质积累，这 与患者预后降低有关，与原发肿瘤相比，转移的患者更多。 此外，在原发肿瘤中肥胖增加的缺氧，导致持续增加的 复氧后特定基因的表达，一种低氧记忆。我们的结果表明，低氧 记忆导致脂肪酸合成酶(FASN)的表达，这是脂肪酸的限速步骤 合成，和丙酮酸羧基酶(PC)，这是我们已经证明提供氧化应激保护。在……里面 此外，炎症细胞因子白介素6(IL-6)在肥胖症中升高，促进了该基因的表达 在CPT1a中，脂肪酸氧化(FAO)供应能量的限速步骤。我们的初步数据显示， 这三种蛋白质的表达及其在脂肪酸合成和增加中的功能后果 与原发肿瘤相比，粮农组织在转移性肿瘤中的比例升高。因此，我们的初步结果表明 低氧可能会导致脂代谢紊乱，从而增加脂的合成和利用 与脂质积累的平衡同时发生。然而，功能失调的脂质的影响 肥胖驱动的转移中的代谢尚不清楚，尽管有支持证据表明缺氧和IL-6是 肥胖症加重。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。他们将检验这一假设，即肥胖与 低氧记忆的增加和促炎IL-6信号的共同作用增加了FA的积累 (FASN)、FAO(CPT1)和细胞存活(PC)以促进转移。这些假说将通过 完成以下两个目标：1)确定低氧记忆对大鼠脑内脂质积累的影响 肥胖驱动的转移，2)建立低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 以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.