Investigating Environmental Risk Factors for Breast Cancer Using Adductomics

使用加成组学研究乳腺癌的环境危险因素

• 批准号: 10540755
• 负责人: William E Funk
• 金额: $ 62.99万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-11 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540755
• 关键词: Address; Air Pollution; Alcohol consumption; Biological; Biological Markers; Blood; Body Size; Breast; Breast Cancer Risk Factor; Cancer Biology; Cancer Etiology; Chemicals; Cohort Studies; Complex; Computer software; Custom; Data; Diagnosis; Dose; ERBB2 gene; Environment; Environmental Exposure; Environmental Pollutants; Environmental Risk Factor; Exposure to; Goals; Home; Human; Incidence; Institute of Medicine (U.S.); Intervention; Link; Lipid Peroxidation; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Menopausal Status; Methodology; Modeling; Nature; Nitrogen Dioxide; Oxidation-Reduction; Oxidative Stress; Participant; Pathway interactions; Plasma; Prospective cohort; Proteins; Public Health; Random Allocation; Reproductive History; Research; Resolution; Response Latencies; Risk Factors; Role; Sampling; Science; Serum Albumin; Sister; Smoking; Source; Time; Woman; adduct; biomarker discovery; breast cancer diagnosis; cancer biomarkers; cancer diagnosis; cancer epidemiology; cancer subtypes; coarse particles; cohort; design; experimental study; fine particles; forging; insight; interest; malignant breast neoplasm; modifiable risk; novel marker; novel strategies; prospective; residence; response; secondary analysis; time use; tool; tumor progression

PROJECT SUMMARY/ABSTRACT Despite years of research, few modifiable risk factors for breast cancer have been identified and the incidence of breast cancer remains high with over 260,000 new cases estimated to arise this year. Established risk factors, such as a woman's reproductive history, body size, smoking, and alcohol intake, are estimated to explain only about half of breast cancer cases. In addition, the underlying biological mechanisms linking environmental risk factors and breast cancer are complex and are not well understood. As a result, new approaches are required that can help identify environmental causes of breast cancer. In this proposal, we apply a novel biomarker approach using protein adduct profiles (i.e., adductomics) to investigate associations between environmental exposures and breast cancer risk in the Sister Study. Because the Sister Study is a nationwide prospective cohort that was specifically designed to investigate environmental risk factors for breast cancer, it is an ideal cohort to investigate the hypotheses outlined in this proposal. We will focus specifically on Cys34 adducts of human serum albumin (HSA-Cys34), which is a nuecleophilic “hotspot” on HSA that scavenges reactive electrophiles from circulating blood arising from both exogenous and endogenous sources. We will first use an untargeted adductomics approach in our discovery experiments using high-resolution mass spectrometry to identify new adduct features. We will then employ a complementary targeted adductomics approach with enhanced analytical sensitivity and higher sample throughput to measure adduct profiles in stored plasma samples collected at baseline from 1,800 incident breast cancer cases and a random sample of 1,800 Sister Study participants. Adducts will be compared across groups to identify discordant adducts, and we will use time-to-diagnosis in our regression models to help differentiate between causal and responsive breast cancer biomarkers. Analyses will also be performed to investigate associations specificto breast cancer subtypes defined by ER/PR and HER2 status.Finally, we will perform secondary analyses and investigate associations between HSA-Cys34 adducts and environmental exposures using existing air pollution exposure data. To achieve our study goals, we will integrate methodological and conceptual tools from the fields of exposure science, cancer epidemiology, and cancer biology to forge a transdisciplinary approach for investigating environmental risk factors for breast cancer. This project has the potential for high impact by potentially identifying modifiable risk factors for breast cancer, and identifying underlying biological pathways linking the environment and breast cancer etiology.

项目总结/摘要 尽管多年的研究，很少有可改变的乳腺癌风险因素已被确定， 乳腺癌的发病率仍然很高，估计今年将出现超过26万例新病例。既定风险 据估计，女性的生育史、体型、吸烟和饮酒等因素 仅能解释一半的乳腺癌病例。此外，潜在的生物学机制连接 环境风险因素与乳腺癌之间的关系十分复杂，人们对此并不十分了解。因此，新 需要能够帮助识别乳腺癌的环境原因的方法。 在这个提议中，我们应用了一种新的生物标志物方法，使用蛋白质加合物谱（即，内收管切开术）， 在姐妹研究中调查环境暴露与乳腺癌风险之间的关联。因为 姐妹研究是一项全国性的前瞻性队列研究，专门用于调查环境 乳腺癌的危险因素，这是一个理想的队列研究中提出的假设概述。我们 将特别关注人血清白蛋白的Cys 34加合物（HSA-Cys 34），这是一种亲核蛋白， HSA上的“热点”，其从循环血液中清除由外源性和外源性 内源性来源。我们将首先在我们的发现实验中使用非靶向内收切断术方法 使用高分辨率质谱来鉴定新的加合物特征。然后我们将使用一个 具有增强的分析灵敏度和更高的样本量的互补靶向内收体切除术方法 从1，800起事件中基线收集的储存血浆样本中测量加合物分布的通量 乳腺癌病例和1,800名姐妹研究参与者的随机样本。加合物将在 组来识别不一致的加合物，我们将在我们的回归模型中使用诊断时间来帮助 区分因果性和反应性乳腺癌生物标志物。还将进行分析， 研究ER/PR和HER 2状态定义的乳腺癌亚型的特异性相关性。最后，我们将 进行二次分析，并调查HSA-Cys 34加合物与环境之间的关联 使用现有的空气污染暴露数据。为了实现我们的学习目标，我们将整合 来自暴露科学、癌症流行病学和癌症领域的方法和概念工具 生物学建立一个跨学科的方法来调查乳腺癌的环境风险因素。这 该项目通过潜在地确定乳腺癌的可改变的风险因素，具有产生高影响的潜力， 确定环境与乳腺癌病因学之间的潜在生物学途径。