Characterization of Altered Fatty Acid Trafficking in Triple-Negative Breast Cancer

项目摘要/摘要 乳腺癌是年内确诊最多的癌症类型，也是癌症相关死亡的第二大原因。 美国的女性。对于包括大多数诊断的受体阳性(RP)亚型， 与其他干预措施相比，临床干预在很大程度上有效地限制了相关死亡率 癌症。然而，剩下的20%，包括三阴性乳腺癌(TNBC)亚型，缺乏 已知的治疗靶点，在临床上是最具挑战性的。 癌症发生时，新陈代谢会发生改变。然而，靶向代谢的疗效在 癌症依赖于对特定癌基因背景下的代谢失调的理解。我们的实验室 另一些研究表明，c-myc(Myc)的水平，一种动态调节许多 在转化过程中，大多数TNBC的细胞功能都增强了。众所周知，MYC负责监管 葡萄糖和谷氨酰胺在癌症中的代谢，但我们的实验室已经表明，MYC调节另一个重要的 生物能量途径，脂肪酸氧化(FAO)，在TNBC。MYC过表达的TNBC显示模型 粮农组织抑制后生物能量代谢和原发肿瘤生长降低，表明新的依赖 在那条路上。在这里，我们建议调查TNBC如何允许增加粮农组织。 粮农组织的增加需要改变脂肪酸(FA)的供应，以及脂肪酸贩运的一个组成部分， 脂肪酸结合蛋白5(FABP5)在TNBC中以MYC依赖的方式上调。FABP是脂类 结合胞质FA和其他分子的伴侣，并可进入一系列细胞室。我们的 研究表明，在MO-TNBC中FABP5的缺失足以导致细胞代谢和增殖的缺陷。 FABP5可能通过促进线粒体FA供应的增加而促进FAO的改变和增殖 以允许增加氧化。我们推测FABP5增加了FA向线粒体的运输 以多年期依赖的方式促进改变后的粮农组织。因此，我们建议对细胞 TNBC中FA贩运的生物学和生物化学、FABP5监管和粮农组织。我们的战略结合了： 利用高含量显微镜观察FA的体外转运，追踪FA的碳追踪研究 体内和体外代谢，基于质谱学的代谢组学分析，药理学和遗传学 FA运输的扰动，以及条件和构成MO-TNBC细胞系和肿瘤模型。 我们期望，我们对粮农组织在MO-TNBC中的机制的调查将促进对FA如何 新陈代谢在癌症中是受调节的，并可能为临床治疗寻找新的治疗靶点。 具有挑战性的乳腺癌亚型。

PROJECT SUMMARY/ABSTRACT Breast cancer is the most diagnosed cancer type and the second leading cause of cancer-related death in women in the United States. For the receptor positive (RP) subtype comprising the majority of diagnoses, clinical interventions have been largely effective in limiting associated mortality when compared with other cancers. However, the remaining 20%, which comprise the triple-negative breast cancer (TNBC) subtype, lack known therapeutic targets and are the most clinically challenging. Cancers display altered metabolism upon carcinogenesis. However, the efficacy of targeting metabolism in cancer depends upon understanding metabolic dysregulation in the context of a specific oncogene. Our lab and others have shown that levels of c-MYC (MYC), a proto-oncogene that dynamically regulates numerous cellular functions during transformation, are increased in a majority of TNBC. MYC is known to regulate glucose and glutamine metabolism in cancer, but our lab has shown that MYC regulates another important bioenergetic pathway, fatty acid oxidation (FAO), in TNBC. Models for MYC-overexpressing TNBC display decreased bioenergetic metabolism and primary tumor growth upon inhibition of FAO, indicating novel reliance on that pathway. Here, we propose to investigate how TNBC permit increased FAO. Increased FAO necessitates alterations to fatty acid (FA) availability, and one fatty acid trafficking component, fatty acid binding protein 5 (FABP5), is upregulated in TNBC in a MYC-dependent manner. FABPs are lipid chaperones that bind cytosolic FA and other molecules, and can access a range of cellular compartments. Our data indicate that FABP5 loss in MO-TNBC is sufficient to cause defects in cell metabolism and proliferation. FABP5 may contribute to altered FAO and proliferation by facilitating increased FA supply at the mitochondria to permit increased oxidation. We hypothesize that increased trafficking of FA to the mitochondria by FABP5 facilitates altered FAO in a MYC-dependent manner. Accordingly, we propose investigation of the cellular biology and biochemistry of FA trafficking, FABP5 regulation and FAO in TNBC. Our strategy combines: utilization of high-content microscopy to visualize FA trafficking in vitro, carbon-tracing studies to follow FA metabolism in vivo and in vitro, mass spectrometry-based metabolomic analyses, pharmacological and genetic perturbations of FA trafficking, and conditional and constitutive MO-TNBC cell lines and tumor models. We expect that our investigation of mechanisms of FAO in MO-TNBC will advance understanding of how FA metabolism is regulated in cancer, and may identify novel therapeutic targets for the treatment of this clinically challenging breast cancer subtype.