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

项目总结/摘要 乳腺癌是最常见的癌症类型，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， 临床干预在限制相关死亡率方面很大程度上是有效的， 癌的然而，剩下的20%，包括三阴性乳腺癌（TNBC）亚型， 已知的治疗靶点，并且是最具临床挑战性的。 癌症在癌变过程中表现出代谢的改变。然而，靶向代谢在 癌症取决于对特定致癌基因背景下代谢失调的理解。我们实验室 和其他人已经表明，c-MYC（MYC）的水平，一个原癌基因，动态调节许多 在大多数TNBC中，转化期间的细胞功能增加。已知MYC调节 我们的研究表明，MYC在癌症中调节葡萄糖和谷氨酰胺代谢，但我们的实验室已经表明，MYC调节另一个重要的 生物能途径，脂肪酸氧化（FAO），在TNBC。用于MYC过表达TNBC展示的模型 抑制FAO后，生物能代谢和原发性肿瘤生长减少，表明新的依赖性 在这条道路上。在这里，我们建议调查TNBC如何允许增加粮农组织。 增加粮农组织需要改变脂肪酸（FA）的可用性，和一个脂肪酸贩运组成部分， 脂肪酸结合蛋白5（FABP 5）在TNBC中以MYC依赖性方式上调。FABPs是脂质 结合胞质FA和其他分子的分子伴侣，并且可以进入一系列细胞区室。我们 数据表明MO-TNBC中FABP 5的损失足以引起细胞代谢和增殖的缺陷。 FABP 5可能通过促进线粒体FA供应的增加而有助于改变FAO和增殖 以允许增加的氧化。我们推测FABP 5增加了FA向线粒体的运输， 以一种依赖多年期方案的方式促进粮农组织的改革。因此，我们建议研究细胞的 FA运输的生物学和生物化学，FABP 5调节和FAO在TNBC中。我们的战略包括： 利用高含量显微镜观察体外FA运输，碳示踪研究跟踪FA 体内和体外代谢，基于质谱的代谢组学分析，药理学和遗传学 FA运输的扰动，以及条件性和组成性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 癌症中的代谢受到调节，并且可以在临床上确定治疗该疾病的新治疗靶点 挑战乳腺癌亚型。

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.