PA-21-071 for Pathea Bruno to CA260126-01 Identifying a proteomic signature for breast cancer detection in breast milk and serum

项目主任/首席调查员(最后、第一、中间)：Darie，Costel C. 候选人Pathea Bruno的补充申请(PAR-18-714) 资助父母基金CA260126-01：确定用于乳腺癌检测的蛋白质组标记 牛奶和血清。 项目总结 年轻女性(育龄、绝经前)的乳腺癌(BC)与 死亡率，以及目前检测这类妇女BC的方法都有已知的局限性。工具用于 需要准确评估年轻女性的个人BC风险，以确定哪些女性将受益于 其中大部分来自早期的干预。母乳提供了一种检查乳房健康的非侵入性方法。我们 将把定量蛋白质组学应用于一组独特的母乳样本，以确定是否有一组 可用于检测早期乳腺癌和预测哪些女性是乳腺癌的蛋白质(蛋白质组特征) 罹患不列颠哥伦比亚省的风险增加。我们假设母乳中存在一组可供使用的蛋白质 确定患有BC的妇女和年轻时患BC的风险较高的妇女。我们还假设 在母乳中检测到的这组蛋白质也可以在血液中检测到，并用于检测BC 在非哺乳期女性中。我们将识别和量化母乳和血清中的蛋白质组学BC信号 这既是潜在的诊断，也是调节失调的途径和过程的信息 在公元前。在目标1中，我们将使用多反应监测(MRM)方法来开发定量 方法对献血者的乳汁(20vs20)和血清(50vs50)样品中的蛋白质进行定量 与浸润性导管癌(IDC)和匹配的对照组，这已经被确定为调节失调 我们的实验室或其他研究。在目标2中，我们将对相同的牛奶和血清样本进行多肽分析。 我们将通过1)纳液相色谱串联质谱(NanoLC-MS/MS)和2)通过 基质辅助激光解吸电离质谱仪(MALDI-MS)。这两种方法相辅相成 彼此之间。在目标3中，我们将使用生物信息学方法来研究调节失调的细胞的功能 乳汁和血清蛋白及其在BC发生和发展中的作用。我们研究的独特之处 包括对母乳进行蛋白质组学分析，以评估患乳腺癌的风险。蛋白质组的翻译 从局部微环境(乳房)到全身环境(血液)的签名将允许其 在非哺乳期妇女BC检测中的应用。我们的提议可能会影响几项医学和研究 领域：1)预防乳腺癌(一级预防)，2)确定是什么使乳房易患癌症 发展，以及3)确定促进BC生长的生化途径，从而预防 治疗。这一领域的助学金还将培养大量的本科生，并指导他们 走向生物医学领域的职业生涯。 PHS 398/2590(06/09版)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle): Darie, Costel C. Supplement Application (PAR-18-714) for Candidate Pathea Bruno Funded parent grant CA260126-01: Identifying a proteomic signature for breast cancer detection in breast milk and serum. Project summary Breast Cancer (BC) in young women (reproductive age, pre-menopausal) is associated with increased mortality, and current methods of detecting BC in this group of women have known limitations. Tools for accurately assessing personal BC risk in young women are needed to identify the women who will benefit the most from earlier intervention. Breast milk provides a noninvasive way to examine the health of the breast. We will apply quantitative proteomics to a unique collection of breast milk samples to determine if there is a group of proteins (proteomic signature) that can be used to detect early breast cancer and predict which women are at increased risk of developing BC. We hypothesize that a set of proteins exist in breast milk that can be used to identify women with BC and women at increased risk of developing BC at a young age. We also hypothesize that the set of proteins, detected in the breast milk, can also be detected in the blood and be used to detect BC in non-lactating women. We will identify and quantify proteomics BC signatures in breastmilk and serum that are both potential diagnostics and also inform on pathways and processes that are dysregulated in BC. In Aim 1, we will employ a Multiple Reaction Monitoring (MRM) approach to develop a quantitation method and then use it to quantify the proteins in the milk (20 vs 20) and serum (50 vs 50) samples of donors with Invasive Ductal Carcinoma (IDC) and matched controls, which were already identified as dysregulated by our lab or in other studies. In Aim 2, we will perform peptidomics analysis of the same milk and serum samples. We will analyze them by 1) nanoliquid chromatography tandem mass spectrometry (nanoLC-MS/MS) and 2) by Matrix Assisted Laser Desorption Ionization mass spectrometry (MALDI-MS). These two methods complement each other. In Aim 3, we will use bioinformatics approaches to investigate both the function of the dysregulated milk & serum proteins and their role in onset and progression of BC. The unique aspects of our study include proteomics analysis of breast milk for assessing BC risk. Translation of the proteomic signature from a local microenvironment (breasts) to a systemic environment (blood) will then allow its use in the detection of BC in non-lactating women. Our proposal can impact several medical and research areas: 1) to prevent BC (primary prevention), 2) to identify what makes the breast susceptible to cancer development, and 3) to identify the biochemical pathways that facilitate BC growth, leading to preventive treatments. This AREA grant will also train an extensive number of undergraduate students and direct them towards careers in biomedical fields. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page