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

在本申请中，我们提出了几项研究，以大大提高我们对氧化应激和抗氧化剂在乳腺癌发生中的作用的理解。荧光氧化产物的循环水平是整体氧化应激的创新标志，与心血管疾病风险增加有关，但据我们所知，尚未对其与乳腺癌风险的关系进行调查。类胡萝卜素是水果和蔬菜中重要的微量营养素，由于其抗氧化特性，人们对乳腺癌有特别的兴趣。尽管关于饮食摄入的流行病学研究结果不一，但最近的数据显示，血浆类胡萝卜素水平对乳腺癌风险有保护作用。具体来说，6项血浆类胡萝卜素的前瞻性研究中有5项，包括我们自己之前在护士健康研究（NHS）中的工作，发现了与乳腺癌风险显著或暗示的负相关。然而，与风险相关的特定类胡萝卜素在所有研究中并不一致，时间的重要性没有得到很好的解决，亚组分析也不够有力。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。据我们所知，在NHS中，只有对其中1个基因的初步分析研究了它们与血浆类胡萝卜素的相互作用，而没有研究过它们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，我们建议对氧化应激、血浆类胡萝卜素和遗传变异的血浆标志物进行深入的前瞻性研究。在本研究中，我们将利用1989-1990年从32,826名NHS妇女中收集的存档（储存在d -1300C）血液样本；其中18743名妇女在2000年捐赠了第二次样本。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。本研究的一个独特优势是，在2008年第二次采血后确认的约700例病例中，可获得间隔10年收集的两项措施，以检查其在致病过程中的暴露时间。在我们的类胡萝卜素分析中，利用我们先前的数据，我们将有大约2000例1990-2008年诊断的病例，以更彻底地评估特定的类胡萝卜素并进行重要的亚组分析。同样，在遗传分析中，我们将有超过2000个案例来解决抗氧化和类胡萝卜素代谢基因遗传变异的主要影响，以及这些基因、DNA修复基因和血浆标记物之间的相互作用。考虑到前瞻性、广泛的协变量信息和持续的高随访率（血液队列中98%），本研究为调查这些关联提供了理想的环境。我们提出的研究将大大有助于我们理解氧化应激途径与乳腺癌风险之间的关系以及抗氧化剂在防止氧化损伤中的作用。公共卫生相关性：氧化应激可能通过其破坏蛋白质和DNA的能力在乳腺癌的发展中发挥重要作用，而来自体内酶和外部饮食来源的抗氧化剂可能抵消这一潜在的有害途径。本研究将在前瞻性护士健康研究队列中研究血浆氧化应激标志物、血浆类胡萝卜素水平和相关基因遗传变异与乳腺癌风险的关系。确认氧化应激的有害影响和类胡萝卜素的保护作用（可随饮食变化而变化）将具有重要的公共卫生意义。

DESCRIPTION (provided by applicant): 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 -1300C) 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. PUBLIC HEALTH RELEVANCE: Oxidative stress may play an important role in the development of breast cancer through its ability to damage protein and DNA while antioxidants, from both enzymes within the body and external dietary sources, may counteract this potentially harmful pathway. This study will examine the relations of plasma markers of oxidative stress, plasma levels of carotenoids, and genetic variation in related genes with the risk of breast cancer in the prospective Nurses' Health Study cohort. Confirmation of a detrimental effect of oxidative stress and the protective benefit of carotenoids, which are amenable to dietary change, would have important public health implications.