Characterizing Novel Estrogen Biomarkers Implicated in Breast Cancer Initiation

描述（由申请人提供）：项目总结/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，这可能导致DNA突变。最近，Cavalieri及其同事开发了一种检测方法来鉴定尿样中的雌激素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中EDA与其未结合的对应物（雌激素代谢物和结合物[EMC]）的比例更高。进一步的研究表明，EDA：EMC的比例降低，以响应抗氧化剂。该生物标志物代表了用于临床干预的潜在标志物，以及用于旨在复制EDA：EMC比率和乳腺癌的早期发现的前瞻性流行病学研究。然而，在我们在大规模研究中调查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EDA：EMC比率随时间的变化水平。 我们将进行可靠性研究，以调查变异性 的EDA：EMC比率内和之间的个人随着时间的推移。具体而言，我们计划招募33名女性（我们预计其中26名将完成研究），我们将收集8份重复尿样，以计算EDA：EMC比值的人间和人内变异性（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统计学因素对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）。将通过超高效液相色谱/串联质谱法测量尿液EDA和EMC，并将使用代谢物浓度计算EDA：EMC的比值。拟议的研究将是EDA：EMC比率的第一次可靠性研究。这项研究的结果将提供关于EDA：EMC比率的可变性及其作为乳腺癌研究中的生物标志物的潜在用途的重要信息。从这一建议中产生的数据将特别有用的大型，前瞻性的乳腺癌流行病学研究和干预试验，旨在预防乳腺癌的发展。

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.