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

基本信息

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
项目类别：
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

项目摘要

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.

摘要：乳腺癌（BC）历年来的统计数据多次表明，虽然 BC 的发病率白种人 (CA) 女性的死亡率较高，而非洲裔美国 (AA) 女性的 BC 死亡率较高。患者更有可能在较年轻的年龄被诊断为 BC，并且发展为 BC 的可能性也更高侵袭性三阴性 (TN) BC AA TNBC 也被诊断为该疾病的更晚期阶段。与 CA 女性相比，该项目计划解决不同的线粒体重编程问题。考虑到 AA 和 CA TNBC 患者，我们在这里使用调制。 Src 肿瘤通路的激活是代谢重编程的主要读数。表明TNBC细胞对脂肪酸β-氧化（FAO）具有高度的能量依赖性，而FAO是重要的能量依赖性然而，我们最近的分析表明，Src 激活的决定因素是其 Y419 位点的自磷酸化。这种依赖性主要限于 CA TNBC 细胞对FAO抑制剂没有反应。在大多数 CA TNBC 中观察到，FAO 抑制剂不会降低 AA 中的 Src 自磷酸化 TNBC 进一步分析表明，尽管 Src 取决于 AA 和 TCA 的活性。 CA TNBC 细胞（TCA 的乙酰辅酶 A 来源）在这两组之间存在显着差异。该项目计划解决 AA 和 CA TNBC 肿瘤之间的能量依赖差异。初步数据还表明，Myc、丙酮酸羧化酶 (PC) 和精氨基琥珀酸合酶增加 AA TNBC 中的 1 (ASS1) 活性对其增强的精氨酸途径至关重要。转化目的是了解 TCA 抑制剂在 AA TNBC 对 Src 的治疗反应中的作用因此，该项目将提供有关能源依赖和肿瘤的重要信息。 AA TNBC 中的通路激活该项目涉及利用多种 AA 和 CA TNBC 细胞系进行实验，患者来源的异种移植物 (PDX) 模型以及从 AA 和 CA TNBC 获得的未识别 BC 组织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。总体而言，这项研究将提供重要的科学机制。 AA TNBC 患者能量依赖和肿瘤途径调节的种族差异背后。结果可以支持开发针对种族的联合疗法来管理激进的 TNBC。