Oxidative Stree, Antioxidants and Risk of Breast Cancer: A Prospective Analysis

摘要 在这项申请中，我们提出了几项研究，以显著提高我们对 氧化应激和抗氧化剂与乳腺癌的发生。荧光氧化产物的循环水平， 一种全面氧化应激的创新标记，与心血管疾病风险的增加有关 疾病，但据我们所知，尚未被研究与乳腺癌风险有关。类胡萝卜素， 水果和蔬菜中突出的微量营养素，对乳腺癌特别感兴趣，因为 它们的抗氧化性。尽管饮食摄入量的流行病学研究结果喜忧参半， 最近的数据显示，血浆类胡萝卜素水平对乳腺癌风险具有保护作用。具体地说，5% 6项关于血浆类胡萝卜素的前瞻性研究，包括我们之前在护士健康研究中所做的工作 (英国国民健康保险制度)发现与乳腺癌风险呈显著或暗示的负相关。然而，具体的 类胡萝卜素(S)与风险的关系在各个研究中并不一致，时机的重要性也不是 已经得到了很好的解决，亚组分析一直动力不足。最后，我们建议研究 抗氧化酶和类胡萝卜素代谢基因变异与乳腺癌风险的关系 以及这些基因、DNA修复基因和血浆标志物之间的相互作用。致我们的 仅对NHS内的这些基因中的1个进行了事先的初步分析，才调查了与 血浆类胡萝卜素，没有人研究过与氧化应激的相互作用。在NHS队列中，有 存档的血液样本和大量关于乳腺癌危险因素的数据，我们提出了一个深入的， 氧化应激血浆标记物、血浆类胡萝卜素和遗传变异的前瞻性研究。 在这项研究中，我们将使用1989-1990年间收集的存档(保存在d-130？C)的血液样本 国民健康保险制度中有32,826名妇女；其中18,743名妇女在2000年捐献了第二份样本。我们的嵌套病例对照 设计将有效地利用这些预期收集的样本。这项研究的一个独特优势是 两项相隔10年收集的措施的可用性，以检查致病过程中暴露的时间 在2008年第二次采血后确诊的大约700例病例中。我们的类胡萝卜素 分析，利用我们之前的数据，我们将在1990-2008年间诊断出大约2000例到更多 彻底评估特定的类胡萝卜素，并进行重要的亚群分析。同样，在基因上 分析我们将有2000多个案例来解决抗氧化剂和 类胡萝卜素代谢基因，以及这些基因、DNA修复基因和血浆之间的相互作用 记号笔。这项研究为研究这些关联提供了一个理想的背景，因为 自然，广泛的协变量信息，以及持续的高随访率(血液队列中98%)。我们的 拟议中的研究应有助于我们理解氧化应激之间的关系 应激途径与乳腺癌风险以及抗氧化剂在保护氧化损伤中的作用。

Abstract In this application, we propose several studies to substantially improve our understanding of the role of oxidative stress and antioxidants in breast carcinogenesis. Circulating levels of fluorescent oxidation products, an innovative marker of overall oxidative stress, have been associated with an increased risk of cardiovascular disease, but to our knowledge, have not been investigated in relation to breast cancer risk. Carotenoids, prominent micronutrients in fruits and vegetables, have been of specific interest in breast cancer because of their antioxidant properties. Although findings from epidemiologic studies of dietary intake have been mixed, recent data have shown a protective effect of plasma carotenoid levels on breast cancer risk. Specifically, 5 of 6 prospective studies of plasma carotenoids, including our own previous work in the Nurses' Health Study (NHS), found significant or suggestive inverse associations with breast cancer risk. However, the specific carotenoid(s) associated with risk has not been consistent across studies, the importance of timing has not been well addressed, and subgroup analyses have been underpowered. Finally, we propose to examine the association between breast cancer risk and variation in antioxidant enzyme and carotenoid metabolism genes, and the interactions between these genes, as well as DNA repair genes, and the plasma markers. To our knowledge only a prior initial analysis of 1 of these genes within the NHS has investigated the interactions with plasma carotenoids, and none has examined the interactions with oxidative stress. Within the NHS cohort, with archived blood samples and a wealth of data on breast cancer risk factors, we propose an in depth, prospective investigation of plasma markers of oxidative stress, plasma carotenoids, and genetic variation. In this study, we will utilize archived (stored at d -130¿C) blood samples collected in 1989-1990 from 32,826 women in the NHS; 18,743 of these women donated a 2nd sample in 2000. Our nested case-control design will efficiently utilize these prospectively collected samples. A unique strength of this study is the availability of 2 measures collected 10 years apart to examine the timing of exposure in the pathogenic process among approximately 700 cases confirmed after the 2nd blood collection through 2008. In our carotenoids analyses, utilizing our prior data, we will have approximately 2000 cases diagnosed 1990-2008 to more thoroughly assess specific carotenoids and conduct important subgroup analyses. Similarly, in the genetic analyses we will have over 2000 cases to address the main effects of genetic variation in antioxidant and carotenoid metabolism genes, as well as interactions between these genes, DNA repair genes, and the plasma markers. This study provides an ideal context in which to investigate these associations, given the prospective nature, extensive covariate information, and an ongoing, high rate of follow-up (98% in the blood cohort). Our proposed study should contribute substantially to our understanding of the relationships between the oxidative stress pathway and breast cancer risk and the role of antioxidants in protecting against oxidative damage.