RACIAL DISPARITY IN THE ENERGY DEPENDENCY OF TRIPLE NEGATIVE BREAST CANCER

摘要：多年来乳腺癌(BC)的统计数据一再表明，虽然BC的发病率是 高加索(CA)女性的死亡率更高，非裔美国人(AA)女性死于BC的比例也更高。重要的是，AA 患者更有可能在更年轻的时候被诊断为BC，并有更高的发展几率 侵略性三重否定(TN)BC。再障TNBC也被诊断为疾病的更晚期。 与CA女性相比。该项目计划解决线粒体重新编程之间的差异 AA和CA TNBC患者。考虑到我们之前的出版物和初步数据，这里我们使用调制 在作为代谢重编程的主要读数的Src的激活上。我们之前已经 表明TNBC细胞对脂肪酸β氧化(FAO)有很高的能量依赖性，而FAO是 Src在其Y419位点上自动磷酸化激活的决定因素。然而，我们最近的分析表明， 这种依赖主要限于CA TNBC。AA TNBC细胞对粮农组织抑制剂的反应不是 观察到大多数CA、TNBC和FAO抑制剂不会减少AA中的Src自磷酸化 TNBC。进一步的分析表明，尽管Src依赖于AA和TCA中的Krebs Cycle(TCA)活性 TCA乙酰辅酶A的来源CA TNBC细胞在两组间有显著差异。因此，这一点 该项目正在计划解决AA和CA TNBC肿瘤之间对能量依赖的差异。我们的 初步数据还表明，Myc、丙酮酸羧化酶(PC)和精氨酸琥珀酸合成酶增加 AA TNBC的1(ASS1)活性在其增强的精氨酸途径中起关键作用。我们还提出了一项 翻译目的：了解TCA抑制剂在AA-TNBC对Src治疗反应中的作用 抑制剂。因此，该项目将提供关于能源依赖和经济合作的关键信息。 再生障碍性鼻咽癌的通路激活。该项目涉及利用几个AA和CA TNBC细胞系进行实验， 患者来源的异种移植(PDX)模型以及从AA和CA TNBC获得的已识别BC组织 病人。该项目还涉及基因组学、蛋白质组学、代谢组学、生物信息学和临床方法。 包括动物模型的活体研究。总体而言，这项研究将提供一个重要的科学机制 再生障碍性鼻咽癌患者能量依赖和肿瘤通路调节的种族差异。这个 结果可以支持开发针对种族的联合疗法来管理 积极进取的TNBC。

Abstract: Breast cancer (BC) statistics over the years have repeatedly shown that while BC incidence is higher in Caucasian (CA) women, death due to BC is higher in African American (AA) women. Importantly, AA patients are more likely to be diagnosed of BC at a younger age and have a higher probability of developing aggressive triple negative (TN) BC. AA TNBC is also diagnosed with a more advanced stage of the disease compared to CA women. This project plans to address the differential mitochondrial reprogramming between AA and CA TNBC patients. Considering our previous publication and preliminary data, here we use modulation in the activation of Src oncopathway as a major readout of metabolic reprogramming. We have previously showed that TNBC cells have high energy dependency to fatty acid β-oxidation (FAO) and FAO is an important determinant of Src activation by autophosphorylation at its Y419 site. However, our recent analyses suggest that this dependency is mostly restricted to CA TNBC. AA TNBC cells are not responding to FAO inhibitors as observed with most of the CA TNBC, and FAO inhibitors do not decrease Src autophosphorylation in AA TNBC. Further analysis suggest that, even though Src depends on Krebs cycle (TCA) activity in both AA and CA TNBC cells, the source of acetyl-CoA for TCA is significantly different between these two groups. Thus, this project is planning to address the disparity in energy dependency between AA and CA TNBC tumors. Our preliminary data also suggest that increased Myc, pyruvate carboxylase (PC) and argininosuccinate synthase 1 (ASS1) activities in AA TNBC are critical in their enhanced arginine pathway. We have also proposed a translational aim to understand the role of TCA inhibitors in the therapeutic response of AA TNBC to Src inhibitors. Thus, this project will provide critical information regarding the energy dependency and onco- pathway activation in AA TNBC. The project involves experiments utilizing several AA and CA TNBC cell lines, patient-derived xenografts (PDX) models as well as deidentified BC tissues obtained from AA and CA TNBC patients. This project also involves genomic, proteomic, metabolomic, bioinformatic and clinical approaches including in vivo studies in animal models. Overall, this study will provide an important scientific mechanism behind the racial disparity of energy dependency and regulation of onco-pathways in AA TNBC patients. The outcome can support in the development of race-specific combination therapies for the management of aggressive TNBC.