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

摘要 在本申请中，我们提出了几项研究，以大大提高我们的理解的作用， 乳腺癌发生中的氧化应激和抗氧化剂。荧光氧化产物的循环水平， 作为整体氧化应激的创新标志物，与心血管疾病风险增加有关。 疾病，但据我们所知，尚未调查与乳腺癌风险的关系。类胡萝卜素， 水果和蔬菜中的主要微量营养素，一直对乳腺癌特别感兴趣，因为 它们的抗氧化特性。虽然饮食摄入的流行病学研究结果好坏参半， 最近的数据表明，血浆类胡萝卜素水平对乳腺癌风险具有保护作用。具体来说，5 6项血浆类胡萝卜素的前瞻性研究，包括我们自己以前在护士健康研究中的工作 (NHS)，发现与乳腺癌风险有显著或暗示性的负相关。但具体 类胡萝卜素与风险相关的研究并不一致，时机的重要性也不一致。 已经得到很好的解决，亚组分析的效力不足。最后，我们建议研究 乳腺癌风险与抗氧化酶和类胡萝卜素代谢基因变异之间的关联， 以及这些基因之间的相互作用，以及DNA修复基因和血浆标记物。对我们 只有在NHS内对这些基因中的一个进行了先前的初步分析，才研究了与 血浆类胡萝卜素，没有人检查过与氧化应激的相互作用。在NHS队列中， 存档的血液样本和大量关于乳腺癌风险因素的数据，我们提出了一个深入的， 氧化应激、血浆类胡萝卜素和遗传变异的血浆标志物的前瞻性研究。 在本研究中，我们将使用1989-1990年从以下患者采集的存档（储存在d-130 ℃）血样： 32 826名妇女参加了国民保健服务;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前瞻性收集的样本。这项研究的一个独特优势是， 间隔10年收集的2项措施的可用性，以检查致病过程中的暴露时间 在2008年第二次采血后确认的约700例病例中。在我们的类胡萝卜素中 分析，利用我们以前的数据，我们将有大约2000例诊断1990-2008年到更多 彻底评估特定的类胡萝卜素，并进行重要的亚组分析。同样，在遗传学中， 分析，我们将有超过2000例，以解决抗氧化剂和抗氧化剂的遗传变异的主要影响， 类胡萝卜素代谢基因，以及这些基因之间的相互作用，DNA修复基因，和血浆 标记。这项研究提供了一个理想的背景下，调查这些协会，鉴于前瞻性的 性质、广泛的协变量信息和持续的高随访率（血液队列中为98%）。我们 拟议的研究应该有助于我们理解氧化之间的关系， 压力途径和乳腺癌风险以及抗氧化剂在保护免受氧化损伤中的作用。

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.