RACIAL DISPARITY IN THE ENERGY DEPENDENCY OF TRIPLE NEGATIVE BREAST CANCER

三阴性乳腺癌能量依赖的种族差异

• 批准号: 10643846
• 负责人: Benny Abraham Kaipparettu
• 金额: $ 35.87万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643846
• 关键词: Acetyl Coenzyme A; Address; African American; Age; Animal Model; Arginine; Aspartate; Benign; Bioinformatics; Biology; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; Cancer Patient; Caucasians; Cells; Cessation of life; Characteristics; Citric Acid Cycle; Clinical; Clinical Data; Combined Modality Therapy; Dasatinib; Data; Dependence; Development; Diagnosis; Disease; Disparity; Drug Targeting; Drug resistance; Exhibits; Fatty Acids; Genomics; Glucose; In Vitro; Incidence; Link; Longterm Follow-up; Malignant Neoplasms; Mediating; Metabolic; Metabolic Activation; Metabolic Pathway; Mitochondria; Modeling; Neoplasm Metastasis; Nitric Oxide; Nuclear; Oncogenic; Outcome; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Polyamines; Population; Positioning Attribute; Probability; Property; Proteomics; Publications; Publishing; Pyruvate; Pyruvate Carboxylase; Race; Regulation; Reporting; Research Personnel; Risk; Role; SRC gene; Sampling; Severities; Site; Socioeconomic Factors; Source; Specificity; Therapeutic; Tissue Microarray; Tissues; Tumor Promotion; Tumor Tissue; Validation; Woman; Work; argininosuccinate synthase; bioinformatics pipeline; breast cancer diagnosis; c-myc Genes; cancer statistics; druggable target; ethnic difference; experience; experimental study; high risk; in vivo; inhibitor; malignant breast neoplasm; metabolic abnormality assessment; metabolomics; mortality risk; multiple omics; oxidation; patient derived xenograft model; preclinical evaluation; preclinical study; prevent; racial disparity; stemness; targeted treatment; translational approach; treatment response; triple-negative invasive breast carcinoma; tumor; tumor progression; tumorigenesis; urea cycle

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.

翻译后摘要：乳腺癌（BC）多年来的统计数据一再表明，虽然BC的发病率是 在白人（CA）女性中，由于BC导致的死亡在非洲裔美国人（AA）女性中更高。重要的是，AA 患者更有可能在年轻时被诊断出患有BC，并且有更高的可能性发展为 三阴性（TN）BC。AA TNBC也被诊断为疾病的更晚期阶段 与女性相比。该项目计划解决差异线粒体重编程之间 AA和CA TNBC患者。考虑到我们以前的出版物和初步数据，在这里我们使用调制 在Src肿瘤通路的激活中作为代谢重编程的主要读数。我们先前已经 显示TNBC细胞对脂肪酸β-氧化（FAO）具有高能量依赖性，并且FAO是重要的 在Y 419位点通过自身磷酸化激活Src的决定子。然而，我们最近的分析表明， 这种依赖性主要限于CA TNBC。AA TNBC细胞不响应FAO抑制剂， 在大多数CA TNBC中观察到，FAO抑制剂不降低AA中Src自磷酸化 TNBC。进一步的分析表明，即使Src依赖于三羧酸循环（TCA）的活动，在AA和 在CA TNBC细胞中，TCA的乙酰辅酶A来源在这两组之间显著不同。因此，这 该项目计划解决AA和CA TNBC肿瘤之间能量依赖性的差异。我们 初步数据还表明，增加Myc，丙酮酸羧化酶（PC）和乙酰氨基琥珀酸合酶， 1（ASS 1）活性在其增强的精氨酸途径中至关重要。我们还提出了一个 翻译目的是了解TCA抑制剂在AA TNBC对Src的治疗反应中的作用 抑制剂的因此，该项目将提供有关能源依赖和肿瘤的关键信息。 在AA TNBC中的通路活化。该项目涉及利用几种AA和CA TNBC细胞系的实验， 患者来源的异种移植物（PDX）模型以及从AA和CA TNBC获得的去识别的BC组织 患者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 包括动物模型的体内研究。总的来说，这项研究将提供一个重要的科学机制， 在AA TNBC患者中能量依赖和肿瘤通路调节的种族差异背后。的 结果可以支持种族特异性联合治疗的发展， 侵略性的TNBC。