Racial disparity in triple-negative breast cancer lipid metabolism

点击翻译按钮获取中文摘要

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.