Investigating Environmental Risk Factors for Breast Cancer Using Adductomics

项目摘要/摘要 尽管多年来的研究，几乎没有发现乳腺癌的可改变的危险因素和发病率 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、吸烟和饮酒等因素会导致 只解释了大约一半的乳腺癌病例。此外，潜在的生物机制联系 环境风险因素和乳腺癌是复杂的，而且还没有被很好地理解。因此，新的 需要能够帮助确定乳腺癌的环境原因的方法。 在这项建议中，我们应用一种新的生物标记物方法，使用蛋白质加合物图谱(即，加合物)来 在Sister研究中，调查环境暴露与乳腺癌风险之间的关系。因为 Sister研究是一项全国性的前瞻性队列研究，专门设计用于调查环境 对于乳腺癌的危险因素，这是一个理想的队列来研究这项建议中概述的假设。我们 将特别关注人血清白蛋白的Cys34加合物(HSA-Cys34)，它是一种嗜核细胞 人血清白蛋白上清除外源性和外源性血液中活性亲电体的“热点” 内生性来源。我们将首先在我们的发现实验中使用一种非定向的内收切除法。 使用高分辨率质谱学来鉴定新的加合物特征。然后，我们将聘请一名 具有更高分析灵敏度和更高样本量的互补靶向外收进取法 测量1800起事件中基线收集的存储血浆样本中加合物分布的吞吐量 乳腺癌病例和1800名姐妹研究参与者的随机样本。加合物将在以下方面进行比较 我们将在回归模型中使用诊断时间来帮助 区分因果和反应性乳腺癌生物标记物。还将执行分析以 调查ER/PR和HER2状态定义的乳腺癌亚型之间的特定关联。最后，我们将 进行二次分析并调查HSA-Cys34加合物与环境之间的关联 利用现有的空气污染暴露数据进行暴露。为了实现我们的学习目标，我们将整合 接触科学、癌症流行病学和癌症领域的方法和概念工具 生物学为研究乳腺癌的环境风险因素打造了一种跨学科的方法。这 该项目有可能通过确定乳腺癌的可改变的风险因素而产生巨大的影响，以及 确定将环境和乳腺癌病因学联系起来的潜在生物学途径。

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.