The Vitamin D Pathway and Mammographic Breast Density in Postmenopausal Women

摘要：实验室研究表明，维生素D具有多种化学预防特性。然而，探究维生素D对乳腺癌风险影响的流行病学数据有限且不一致。虽然许多研究都评估了饮食摄入量，但很少有研究直接测量血液中维生素D水平与乳腺癌风险的关系。没有人在其他分子的全面背景下研究维生素D，比如视黄醇，实验室研究表明视黄醇会影响维生素D对乳腺细胞的作用。此外，具有化学预防或有丝分裂特性的维生素D下游靶点，如甲状旁腺激素和IGF-1，本身可能影响乳腺癌风险。本研究的目的是评估维生素D途径与乳房x线摄影乳房密度的关系，乳房密度是乳腺癌风险的中间标记。我们建议1)检查乳腺x线摄影密度与血液维生素D水平之间的关系；2)确定甲状旁腺激素、IGF-1和IGFBP-3在介导维生素D与密度之间关系中的潜在作用；3)确定乳腺x线摄影密度与维生素D之间的关系是否受到血液中视黄醇或钙水平的影响。为了实现这些目标，我们建议在现有的研究中增加额外的暴露评估，评估270名在威斯康星大学麦迪逊分校诊所接受乳房x光筛查的健康绝经后妇女的乳房密度。这项现有研究的数据收集包括乳腺癌风险因素问卷和血液样本，都是在乳房x光检查时获得的。乳房x线摄影密度将被评估为一个连续的线性函数测量百分比密度，使用计算机辅助方法（Cumulus软件）。我们建议通过测量血清维生素D [25(OH)D]、甲状旁腺激素、IGF-1、IGFBP-3、视黄醇和钙的水平来补充现有的研究。统计学方法将用于确定乳腺x线摄影密度与维生素D之间的关系，甲状旁腺激素、IGF-1和IGFBP-3的潜在介导作用，以及视黄醇和钙的潜在调节作用。在母体研究中加入维生素D暴露评估将有效地利用现有的研究基金投资。通过使用连续尺度的乳房x线摄影密度作为中间标记，本研究提供了一种有效的设计，具有强大的能力来检测乳腺密度与潜在重要和可改变的维生素D途径分子水平之间的关联。由于维生素D不足在美国很普遍，而且越来越多，阐明维生素D与乳腺癌风险相关性的证据可能为乳腺癌预防提供重要的策略。

DESCRIPTION (provided by applicant): The Vitamin D Pathway and Mammographic Breast Density in Postmenopausal Women Abstract Laboratory studies have demonstrated that Vitamin D has a number of chemopreventive properties. However, epidemiologic data exploring the effects of Vitamin D on breast cancer risk are limited and inconsistent. While many studies have assessed dietary intake, fewer have directly measured blood levels of Vitamin D in relation to breast cancer risk. None have explored Vitamin D in the full context of other molecules, such as retinol, which laboratory studies suggest influence the effect of Vitamin D on breast cells. Further, downstream targets of Vitamin D with chemopreventive or mitogenic properties, such as parathyroid hormone and IGF-1, may themselves influence breast cancer risk. The objective of this study is to evaluate the Vitamin D pathway in relation to mammographic breast density, an intermediate marker of breast cancer risk. We propose to 1) examine the relation between mammographic density and blood levels of Vitamin D; 2) determine the potential role of parathyroid hormone, IGF-1, and IGFBP-3 in mediating the association between Vitamin D and density; and 3) determine if the relation between mammographic density and Vitamin D is modified by blood levels of retinol or calcium. To accomplish these aims, we propose to add additional exposure assessment to our existing research study evaluating breast density among 270 healthy postmenopausal women attending University of Wisconsin-Madison Clinics for a screening mammogram. Data collection for this existing study includes a breast cancer risk factor questionnaire and a blood sample, both obtained at the time of the mammogram. Mammographic density will be assessed as a continuous linear function measuring percent density, using a computer-assisted method (Cumulus software). We propose to supplement this existing study by measuring serum levels of Vitamin D [25(OH)D], parathyroid hormone, IGF-1, IGFBP-3, retinol, and calcium. Statistical methods will be used to determine the relation between mammographic density and Vitamin D, the potential mediating roles of parathyroid hormone, IGF-1, and IGFBP-3, and the potential modifying effects of retinol and calcium. Adding Vitamin D exposure assessment to the parent study will effectively leverage existing investment of research funds. By using mammographic density on a continuous scale as an intermediate marker, this study offers an efficient design with strong power to detect an association between breast density and levels of potentially important and modifiable Vitamin D pathway molecules. Since Vitamin D insufficiency in the United States is widespread and increasing, evidence elucidating the relevance of Vitamin D to breast cancer risk may point to important strategies for breast cancer prevention. PUBLIC HEALTH RELEVANCE: The Vitamin D Pathway and Mammographic Breast Density in Postmenopausal Women Narrative Laboratory studies have demonstrated that Vitamin D has anti-carcinogenic properties, and breast tissue is known to contain Vitamin D receptors. We plan to measure blood levels of Vitamin D and other molecules which interact with Vitamin D in a group of 270 women who are already enrolled in a study of mammographic breast density. Since breast density is a strong intermediate marker of breast cancer risk, an association between Vitamin D and breast density would suggest a potential role for Vitamin D in the prevention of breast cancer.