Circulating fatty acids and breast cancer risk: a prospective study

描述(申请人提供)：在这项申请中，我们提出了几项研究，以显著提高我们对来自饮食和内源性生产的脂肪酸在乳腺癌发生中的作用的理解。长期以来，饮食脂肪一直被认为会增加乳腺癌的风险，但在大多数大型前瞻性研究中，并没有观察到总体上的联系。尽管饮食脂肪摄入量作为暴露的限制，但与特定类型的脂肪(例如，动物脂肪和反式脂肪)和/或在特定的妇女亚群中(例如， 绝经前)在一些研究中被观察到。生物标志物可能会更准确地反映饮食中脂肪酸的内部剂量，并允许检查内源性合成的脂肪酸，这些脂肪酸构成了内部接触脂肪酸的重要组成部分。我们建议在护士健康研究II(NHSII)内的嵌套病例对照研究中测量红细胞脂肪酸，NHSII是一个已建立的年轻女性队列。首先，我们将评估反映乳制品脂肪和肉类摄入量的饱和脂肪酸和反式脂肪酸之间的关系(15：0， 从部分氢化油中提取的反式脂肪酸(18：1和18：2)具有患乳腺癌的风险。我们还将评估与n-3和n-6多不饱和脂肪酸的关系。为了进一步探索可能的机制，我们将检查这些特定脂肪酸与肿瘤组织炎症标记物过度表达的相关性。接下来，我们将讨论内源合成脂肪酸的一个重要组成部分--9-去饱和酶的活性。硬脂酰辅酶A去饱和酶1(SCD1)，通过特定饱和脂肪酸与单不饱和脂肪酸的比率(饱和指数(SI)n-7和SIN-9)来测量。实验证据表明，SCD1在乳腺肿瘤的生长中很重要，迄今为止有限的流行病学证据表明，SCD1活性越高，乳腺癌的风险就越高。我们将进一步研究这种与肿瘤过度表达脂肪酸合成酶(Fas)的关系。我们将利用1996-1999年间从NHSII的29,611名妇女那里收集的存档(储存在d-130？C)血液样本。我们将使用这些血液样本和来自大约75%病例的存档肿瘤组织块进行嵌套病例对照研究。我们预计将有900多例乳腺癌病例，其中包括近500名确诊时已绝经前的妇女，以及200多名在采血时绝经前但确诊时已绝经后的妇女。我们预计大约有600例肿瘤组织。考虑到前瞻性，广泛的协变量信息，存档的血液和组织标本，以及持续的高随访率，这项研究为研究这些相关性提供了一个理想的背景。我们拟议的研究将是对绝经前女性中这些关联的第一次详细评估，并将大大有助于我们理解脂肪酸与乳腺癌风险的关联，可能导致重要的乳腺癌预防建议以及SCD1和Fas通路的新探索途径。 公共卫生相关性：长期以来，脂肪摄入量一直被认为会增加乳腺癌的风险，但队列研究并未显示出与总脂肪的强烈关联。这项建议旨在通过测量血液中的特定脂肪酸来扩大我们对脂肪在乳腺癌病因学中作用的了解，这些特定脂肪酸代表来自肉类和乳制品、加工食品和蔬菜来源的脂肪，这些领域的饮食证据表明存在关联，以及脂肪内部转化与乳腺癌风险的标记。表征这些关联，并进一步探索潜在的机制，将为乳腺癌预防提供重要的知识。

DESCRIPTION (provided by applicant): In this application we propose several studies to substantially improve our understanding of the role of fatty acids, from both diet and endogenous production, in breast carcinogenesis. Dietary fat has long been hypothesized to increase breast cancer risk, but no overall association has been observed in most large prospective studies. Despite the limitations of dietary fat intake as an exposure, associations with specific types of fat (e.g., animal and trans fats) and/or in specific subsets of women (e.g., premenopausal) have been observed in some studies. Biomarkers are likely to reflect the internal dose of dietary fatty acids more closely and allow for an examination of endogenously synthesized fatty acids, which make up a substantial component of internal exposure to fatty acids. We propose to measure erythrocyte fatty acids in a nested case-control study within the Nurses' Health Study II (NHSII), an established cohort of younger women. First, we will assess the association of saturated and trans fatty acids that reflect intake of dairy fat and meat (15:0, 16:1n- 7t, 18:1n-7t) and trans fatty acids from partially hydrogenated oils (18:1 and 18:2) with breast cancer risk. We also will assess the association with n-3 and n-6 polyunsaturated fatty acids. To further explore possible mechanisms, we will examine the associations of these specific fatty acids with tumor tissue over-expression of inflammatory markers. Next, we will address an important component of endogenously synthesized fatty acids, activity of ¿9-desaturase (a.k.a. stearoyl-CoA desaturase 1 (SCD1)), measured by the ratio of specific saturated to monounsaturated fatty acids, (saturation index (SI)n-7 and SIn-9). Experimental evidence suggests SCD1 is important in breast tumor growth and the limited epidemiologic evidence to date suggests an increased breast cancer risk with higher SCD1 activity. We will further investigate this association with tumor over-expression of fatty acid synthase (FAS). We will utilize archived (stored at d -130¿C) blood samples collected in 1996-1999 from 29,611 women in the NHSII. We will conduct a nested case-control study using these blood samples and archived tumor tissue blocks from approximately 75% of cases. We anticipate more than 900 incident cases of breast cancer, including nearly 500 women premenopausal at diagnosis and more than 200 women who were premenopausal at blood collection but postmenopausal at diagnosis. We expect approximately 600 cases with tumor tissue. This study provides an ideal context in which to investigate these associations, given the prospective nature, extensive covariate information, archived blood and tissue specimens, and an ongoing, high rate of follow-up. Our proposed study will be the first detailed assessment of these associations among premenopausal women and should contribute substantially to our understanding of the associations of fatty acids with breast cancer risk, potentially leading to important recommendations for breast cancer prevention as well as new avenues of exploration in the SCD1 and FAS pathways. PUBLIC HEALTH RELEVANCE: Fat intake has long been hypothesized to increase breast cancer risk, but cohort studies have not shown strong associations with total fat. This proposal seeks to expand our knowledge of the role of fat in breast cancer etiology by measuring specific fatty acids in the blood, representing fats from meat and dairy, processed foods, and vegetable sources, areas where dietary evidence suggests an association, as well as a marker of the internal transformation of fats with breast cancer risk. Characterizing these associations, and further exploring potential mechanisms, will provide important knowledge about breast cancer prevention.