Characterizing Novel Estrogen Biomarkers Implicated in Breast Cancer Initiation

表征与乳腺癌发生有关的新型雌激素生物标志物

• 批准号: 8445138
• 负责人: JOHANNA W LAMPE
• 金额: $ 8.8万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445138
• 关键词: Antioxidants; Biological Assay; Biological Markers; Breast Cancer Prevention; Cancer Intervention; Cancer Patient; Catechol Estrogens; Cell Line; Clinical; Clinical Trials; DNA Adduction; DNA Adducts; Data; Demographic Factors; Development; Epidemiologic Studies; Estrogen Metabolism; Estrogen receptor negative; Estrogens; Future; Gene Mutation; Health; High Risk Woman; Individual; Intervention; Intervention Trial; Investigation; Laboratories; Liquid Chromatography; Literature; Measures; Menstrual cycle; Modeling; Mus; Mutation; Pathway interactions; Persons; Phase; Play; Prevention strategy; Quinones; Rattus; Recruitment Activity; Reporting; Reproductive History; Research; Research Personnel; Research Project Grants; Risk; Role; Sampling; Scientist; Testing; Time; Urine; Woman; abstracting; anticancer research; cancer initiation; cancer prevention; cancer risk; design; genotoxicity; innovation; malignant breast neoplasm; novel; novel marker; prevent; prospective; public health relevance; response; tandem mass spectrometry; uptake; urinary

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT A large accumulation of evidence has implicated estrogen in breast cancer development. One way in which estrogen impacts breast cancer is via the catechol estrogen (CE) metabolism pathway. Particular CE metabolites, namely hydroxy estrogen quinones, are capable of forming DNA adducts which may result in DNA mutations. Recently, Cavalieri and colleagues developed an assay to identify estrogen DNA adducts (EDA) in urine samples. These researchers observed that a ratio of EDA to their unbound counterparts (estrogen metabolites and conjugates [EMC]) was higher in breast cancer patients and those women at high risk of breast cancer compared to low-risk, healthy controls. Additional studies demonstrated that the EDA:EMC ratio was reduced in response to antioxidants. This biomarker represents a potential marker for use in clinical interventions, as well as in prospective, epidemiologic studies aiming to replicate the early findings on the EDA:EMC ratio and breast cancer. However, more research is needed on the EDA:EMC ratio before we move to investigate the EDA:EMC ratio in large-scale studies. First, a reliability study of the EDA:EMC ratio is needed in order to indicate the level of variabiity in the EDA:EMC ratio over time. We will conduct a reliability study to investigate the variability of the EDA:EMC ratio within and between individuals over time. Specifically, we propose to recruit 33 women (of which we anticipate 26 will complete the study) in whom we will collect 8 repeated urine samples in order to calculate the inter- and intra-person variability of the EDA:EMC ratio (Specific Aim 1). As part of the proposed study, we will also explore the influence of health and demographic factors on the EDA:EMC ratio (Secondary Aim 1), as well as to examine the impact of menstrual cycle phase on the EDA:EMC ratio (Secondary Aim 2). Urinary EDA and EMC will be measured by ultraperformance liquid chromatography/tandem mass spectrometry and metabolite concentrations will be used to calculate ratios of EDA:EMC. The proposed study would be the first reliability study of the EDA:EMC ratio. The results of this investigation will provide important information on the variability of the EDA:EMC ratio and its potential use as a biomarker in breast cancer research. Data emanating from this proposal will be particularly useful in the development of large, prospective epidemiologic studies of breast cancer and intervention trials aimed at breast cancer prevention.

描述（由申请人提供）：项目摘要/摘要大量的证据积聚在乳腺癌发育中暗示了雌激素。雌激素影响乳腺癌的一种方法是通过Catechol雌激素（CE）代谢途径。特定的CE代谢产物，即羟基雌激素喹酮，能够形成可能导致DNA突变的DNA加合物。最近，Cavalieri及其同事开发了一种测定法，以鉴定尿液样品中的雌激素DNA加合物（EDA）。这些研究人员观察到，与低风险，健康对照组相比，乳腺癌患者和那些患有乳腺癌高风险的女性的EDA与其未结合对应物（雌激素代谢物和偶联物[EMC]）的比率更高。其他研究表明，EDA：EMC比响应于抗氧化剂而降低。该生物标志物代表了用于临床干预措施以及前瞻性的流行病学研究的潜在标记，旨在复制有关EDA：EMC：EMC比率和乳腺癌的早期发现。但是，在我们研究大规模研究中的EDA：EMC比率之前，需要对EDA：EMC比率进行更多的研究。首先，需要对EDA：EMC比率进行可靠性研究，以表明随着时间的流逝，EDA：EMC比率的变异性水平。 我们将进行可靠性研究以调查可变性 随着时间的流逝，个体内部和个人之间的EDA：EMC比率。具体而言，我们建议招募33名妇女（我们预计将完成26名女性），我们将收集8个重复的尿液样本，以计算EDA：EMC比率的人间和人体内变异性（特定目标1）。作为拟议研究的一部分，我们还将探讨健康和人口统计学因素对EDA：EMC比率（次要目标1）的影响，并研究月经周期阶段对EDA：EMC：EMC比率的影响（次要目标2）。尿EDA和EMC将通过超强化液相色谱/串联质谱法测量，代谢物浓度将用于计算EDA：EMC的比率。拟议的研究将是EDA：EMC比率的首次可靠性研究。这项研究的结果将提供有关EDA：EMC比率及其作为乳腺癌研究生物标志物的潜在用途的重要信息。从该提案中发出的数据将在开发乳腺癌的大型前瞻性流行病学研究和旨在预防乳腺癌的干预试验的发展中特别有用。