Obesity, Metabolism and Breast Cancer Metastasis

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， 最近在癌症发展和进展方面的研究强调了代谢重新编程的作用， 这导致增加了细胞增殖所需的细胞构建块的供应 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，代谢酶丙酮酸羧基酶是 在肥胖期间上调，这种上调与乳腺癌的进展密切相关。 其他研究表明，瘦素是一种脂肪因子，在肥胖期间表达增加，其 受体在转移细胞中的表达增强，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，丙酮酸羧化酶的遗传枯竭显著抑制了 几种同基因小鼠模型中乳腺癌的转移。尽管有证据表明丙酮酸 在肥胖条件下，羧基酶促进乳腺癌转移，其机制是 酶是如何发挥这种作用的，目前还知之甚少。在拟议的研究中，研究小组将评估 丙酮酸羧基酶调节肥胖引起的乳腺癌转移的机制基础。他们 将检验瘦素增加乳房组织丙酮酸羧基酶表达的假说 肥胖状态，丙酮酸羧化酶是细胞外基质迁移和存活的关键 脱离，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来检验：1)定义 PC在肿瘤转移过程中的表达机制；2)阐明PC的代谢机制 促进转移；以及3)建立瘦素调节的PC表达促进 肥胖导致的转移。这些研究的完成将产生有价值的机械信息， 指导未来为超重和肥胖者提供循证建议 这将有助于减少乳腺癌的转移。

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.