Obesity, Metabolism and Breast Cancer Metastasis

项目摘要 虽然有大量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，本发明还 最近对癌症发展和进展的研究强调了代谢重编程的作用， 这导致增加的细胞增殖所必需的细胞构件的供应增加 以及在不断变化的营养和含氧环境中细胞生存所需的适应性。 我们团队和其他人的研究表明，代谢酶丙酮酸羧化酶是 在肥胖期间上调，并且这种上调与乳腺癌进展密切相关。 另外的研究表明，瘦素是一种脂肪因子，在肥胖时表达增加， 受体的表达在转移细胞中增强，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，丙酮酸羧化酶的遗传缺失大大抑制了 乳腺癌转移在几个同基因小鼠模型。尽管有证据表明丙酮酸 羧化酶在肥胖条件下有助于乳腺癌转移，这一机制 酶发挥这种作用仍然知之甚少。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 将测试瘦素增加乳腺组织中丙酮酸羧化酶表达的假设， 丙酮酸羧化酶对于细胞外基质的迁移和存活都是至关重要的 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测试：1）定义 转移过程中PC表达的机制; 2）阐明PC表达的代谢机制， 促进转移; 3）建立瘦素调节PC表达有助于转移的机制。 肥胖导致的转移完成这些研究将产生有价值的机械信息， 指导今后为超重和肥胖者制定循证建议， 这将有助于减少乳腺癌转移。

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.