Racial disparity in triple-negative breast cancer lipid metabolism

项目名称 三阴性乳腺癌脂代谢的种族差异 项目总结 癌症的发病率、进展、耐药性和死亡率因种族和民族的不同而有显著差异。三重- 阴性乳腺癌(TNBC)亚型对非洲裔美国人(AA)女性的影响不成比例 因转移导致的死亡率。最近，肿瘤中脂质代谢的改变被确定为驱动因素 TNBC转移，为我们的中心假设提供了一个合理的理由，即存在基因表达和/或 引起脂代谢变化的AA和高加索白种(CW)群体间的遗传差异 基本的TNBC启动和进展。在赠款的P20试点阶段，我们将针对 假设正常乳腺组织和癌组织中的脂质成分存在差异 AA和CW种群。在细胞水平上，癌细胞可以内源性地改变脂质含量(通过 新陈代谢)或外源性(通过从微环境中吸收脂肪)，但关于 每条途径在脂代谢失调中的作用是缺乏的。在人类人口层面上， 几项全基因组关联研究确定了乳房和乳房脂肪代谢改变的相关性 其他癌症，然而，这些研究中的大多数使用了欧洲血统的患者。因此，患者的种族/民族 分歧仍有待发现。在赠款的P20试点阶段，我们的目标是：1)建立 用于正常乳腺组织(NBT)、肿瘤和正常邻近组织的样品采集和分析管道 (NAT)对，以及2)确定脂组成差异和脂代谢基因表达的变化 配对的NAT和癌症样本，以及AA和CW患者样本。这些目标将有助于 首要目标(在该项目的R03和R01阶段实现)：确定分子 脂质成分差异的机制，这将使我们能够探索变化之间的因果关系 在AA和CW TNBC患者群体中的肿瘤脂代谢和癌症进展。在这里，我们将 在一年内追求两个可行的目标：1)使用脂组分析来确定是否存在种族 非裔美国人和非裔美国人NBT和Tumor/NAT配对TNBC样本的脂组成差异 高加索白人患者；以及2)使用转录特征分析来确定是否存在种族差异 NBT和肿瘤/NAT配对的非洲裔美国人和美国人TNBC中脂代谢基因的表达 高加索白人患者。在P20阶段结束时，我们将生成初步数据，显示有 癌症和NAT之间以及AA和CW种族之间的脂质成分差异； 朝着建立潜在的转录变化迈出的第一步。这将为以下工作提供前提 R03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 过渡到R01应用程序，其中将包括全基因组测序和表观遗传学(CHIP-SEQ)以 找出观察到的脂类和转录体变化的机制细节。归根结底，这一系列研究 将允许针对人群量身定做的预防和治疗。

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.