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 大量积累的证据表明雌激素与乳腺癌的发展有关。雌激素影响乳腺癌的一种方式是通过儿茶酚雌激素 (CE) 代谢途径。特定的 CE 代谢物，即羟基雌激素醌，能够形成 DNA 加合物，从而可能导致 DNA 突变。最近，Cavalieri 及其同事开发了一种检测方法来鉴定尿液样本中的雌激素 DNA 加合物 (EDA)。这些研究人员观察到，与低风险的健康对照组相比，乳腺癌患者和乳腺癌高风险女性的 EDA 与未结合的对应物（雌激素代谢物和结合物 [EMC]）的比率较高。其他研究表明 EDA:EMC 比率因抗氧化剂而降低。该生物标志物代表了一种可用于临床干预以及前瞻性流行病学研究的潜在标志物，旨在复制 EDA:EMC 比率和乳腺癌的早期发现。然而，在我们开始大规模研究 EDA:EMC 比率之前，需要对 EDA:EMC 比率进行更多研究。首先，需要对 EDA:EMC 比率进行可靠性研究，以表明 EDA:EMC 比率随时间的变化程度。 我们将进行可靠性研究来调查变异性 随着时间的推移，个体内部和个体之间的 EDA:EMC 比率。具体来说，我们建议招募 33 名女性（我们预计其中 26 名将完成研究），我们将在其中收集 8 份重复尿液样本，以计算 EDA:EMC 比率的人际和人内变异性（具体目标 1） ）。作为拟议研究的一部分，我们还将探讨健康和人口因素对 EDA:EMC 比率的影响（次要目标 1），以及检查月经周期阶段对 EDA:EMC 比率的影响（次要目标2）。尿液 EDA 和 EMC 将通过超高效液相色谱/串联质谱法进行测量，代谢物浓度将用于计算 EDA:EMC 比率。拟议的研究将是 EDA:EMC 比率的第一个可靠性研究。这项调查的结果将提供有关 EDA:EMC 比率的变异性及其作为乳腺癌研究中生物标志物的潜在用途的重要信息。该提案产生的数据对于开展大规模的乳腺癌前瞻性流行病学研究和旨在预防乳腺癌的干预试验特别有用。