Racial disparity in triple-negative breast cancer lipid metabolism

三阴性乳腺癌脂质代谢的种族差异

• 批准号: 10302796
• 负责人: Olga Valeriyevna Razorenova
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10302796
• 关键词: Address; Affect; African American; Algorithms; Biochemical Pathway; Bioinformatics; Breast; Breast Cancer Patient; Breast Cancer Treatment; Breast cancer metastasis; Candidate Disease Gene; Caucasians; ChIP-seq; Clinical Trials; Code; Collaborations; Data; Development; Diagnosis; Disease; Drug resistance; Enzymes; Epigenetic Process; Ethnic Origin; Etiology; European; First Generation College Students; Freezing; Funding; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Goals; Grant; Human; Incidence; Knowledge; Lecithin; Link; Lipids; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Medical center; Metabolic Pathway; Metabolism; Methods; Molecular; Molecular Biology; Mutation; Neoplasm Metastasis; Ontology; Pathway Analysis; Pathway interactions; Patients; Phenotype; Phosphatidylinositols; Pilot Projects; Play; Population; Prevention therapy; Race; Reproducibility; Research; Sampling; Sampling Studies; Sphingomyelins; Surgeon; Testing; Therapeutic Clinical Trial; Tissue-Specific Gene Expression; Tissues; Training; Woman; cancer cell; cancer initiation; cancer subtypes; career; dietary; differential expression; ethnic difference; fatty acid oxidation; genome sequencing; genome wide association study; health equity; individualized medicine; inhibitor/antagonist; lipid biosynthesis; lipid metabolism; lipidome; lipidomics; mRNA sequencing; malignant breast neoplasm; mortality; patient population; racial and ethnic; racial difference; racial disparity; success; transcriptomics; triple-negative invasive breast carcinoma; tumor; tumor initiation; tumor progression; uptake; whole genome

PROJECT TITLE Racial disparity in triple-negative breast cancer lipid metabolism PROJECT SUMMARY Cancer incidence, progression, drug-resistance, and mortality vary significantly by race and ethnicity. Triple- negative breast cancer (TNBC) subtype disproportionately affects African American (AA) women with high mortality rate due to metastasis. Recently, altered lipid metabolism in the tumor was identified as a driver of TNBC metastasis, providing a rational for our central hypothesis that there are gene expression and/or genetic differences between AA and Caucasian White (CW) populations that cause lipid metabolism changes underlying TNBC initiation and progression. At the P20 pilot stage of the grant we will address a focused hypothesis that there are differences in lipid composition in normal breast tissue and cancer tissue between AA and CW populations. At the cellular level, cancer cells can alter lipid content endogenously (via metabolism) or exogenously (via lipid uptake from their microenvironment), yet knowledge about the contribution of each pathway to lipid metabolism dysregulation is lacking. At the human population level, several genome wide association studies identified associations with lipid metabolism alterations in breast and other cancers, yet, the majority of these studies used patients of European origin. Thus, patient racial/ethnic differences remain to be uncovered. At the P20 pilot stage of the grant, our objectives are 1) to set up the pipeline for sample acquisition and analysis for normal breast tissue (NBT), tumor and normal adjacent tissue (NAT) pairs, and 2) determine lipid composition differences and lipid metabolism gene expression changes in paired NAT and cancer samples, as well as in AA vs. CW patient samples. These objectives will contribute to the overarching goal (achieved at the R03 and R01 stages of this project): to determine the molecular mechanism underlying lipid composition differences, which will enable us to probe causality between changes in tumor lipid metabolism and cancer progression in AA and CW TNBC patient populations. Here we will pursue two Aims feasible within 1 year: 1) Use lipidomic profiling to determine whether there are racial differences in lipid composition of NBT and tumor/NAT paired TNBC samples from African American and Caucasian White patients; and 2) Use transcriptomic profiling to determine whether there are racial differences in lipid metabolism gene expression of NBT and tumor/NAT paired TNBC samples from African American and Caucasian White patients. At the end of the P20 stage we will generate preliminary data showing that there are differences in lipid composition between cancer and NAT as well as between AA and CW racial groups; with the first step made towards establishing underlying transcriptional changes. This will provide premise for an R03 application to link these lipid differences with cancer initiation and progression. Eventually, we will transition to an R01 application, which will include whole genome sequencing, and epigenetics (ChIP-seq) to find mechanistic details of the observed lipidomic and transcriptomic changes. Ultimately, this line of research will allow population-tailored prevention and therapies.

项目名称 三阴性乳腺癌脂质代谢的种族差异 项目摘要 癌症的发病率、进展、耐药性和死亡率因人种和种族而异。三重- 阴性乳腺癌（TNBC）亚型不成比例地影响非洲裔美国人（AA）妇女， 转移导致的死亡率。最近，肿瘤中脂质代谢的改变被确定为肿瘤生长的驱动因素。 TNBC转移，为我们的中心假设提供了合理性，即存在基因表达和/或 AA和高加索白色（CW）人群之间的遗传差异导致脂质代谢变化 潜在的TNBC启动和进展。在P20赠款的试点阶段，我们将解决一个重点 假设在正常乳腺组织和癌组织中， AA和CW人群。在细胞水平上，癌细胞可以内源性地改变脂质含量（通过 代谢）或外源性（通过从其微环境中摄取脂质），但关于 缺乏每种途径对脂质代谢失调的贡献。在人类的层面上， 几项全基因组关联研究确定了乳腺癌和乳腺癌中脂质代谢改变的关联， 然而，这些研究中的大多数使用欧洲血统的患者。因此，患者种族/民族 差异仍有待发现。在P20试验阶段，我们的目标是：1）设立 用于正常乳腺组织（NBT）、肿瘤和正常邻近组织的样本采集和分析的管道 (NAT)对，和2）确定脂质组成的差异和脂质代谢基因表达的变化， 配对的NAT和癌症样品，以及AA与CW患者样品。这些目标将有助于 总体目标（在本项目的R 03和R 01阶段实现）：确定 脂质成分差异的潜在机制，这将使我们能够探测变化之间的因果关系 在AA和CW TNBC患者群体中的肿瘤脂质代谢和癌症进展中。这里我们将 在1年内追求两个可行的目标：1）使用脂质组学分析来确定是否存在种族差异。 来自非裔美国人的NBT和肿瘤/NAT配对TNBC样本的脂质组成差异， 高加索白色患者;和2）使用转录组学分析来确定是否存在种族差异 在来自非裔美国人的NBT和肿瘤/NAT配对TNBC样品的脂质代谢基因表达中， 白人白色患者。在P20阶段结束时，我们将生成初步数据，显示 癌症和NAT之间以及AA和CW种族之间的脂质组成差异; 第一步是建立潜在的转录变化。这将提供前提， R 03应用程序将这些脂质差异与癌症的发生和进展联系起来。最终，我们会的 过渡到R 01应用程序，其中将包括全基因组测序和表观遗传学（ChIP-seq）， 发现所观察到的脂质组学和转录组学变化的机制细节。最终，这一系列的研究 将允许针对人群的预防和治疗。