Secreted Proteins as Breast Cancer Prevention Markers

分泌蛋白作为乳腺癌预防标志物

• 批准号: 7066586
• 负责人: MICHAEL N GOULD
• 金额: $ 35.52万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-03 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7066586
• 关键词: biomarker; biotechnology; breast neoplasms; cancer prevention; clinical research; disease /disorder model; enzyme inhibitors; epidermal growth factor; human therapy evaluation; human tissue; informatics; laboratory rat; mammary epithelium; mammary gland; method development; microarray technology; monoterpenes; neoplasm /cancer pharmacology; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; preneoplastic state; proteomics; retinoate; secretion; serology /serodiagnosis; tamoxifen

DESCRIPTION (provided by applicant) The goal of this project is to develop readily translatable surrogate biomarkers for hormonalty non-responsive breast cancer chemoprevention trials. For this purpose, surrogate biomarkers will be developed, consisting of breast cell (pre-neoplastic, early neoplastic) secreted proteins that can be assayed for in sera or breast nipple aspirate fluids. These secreted protein biomarkers will be identified and validated in a rat retroviral vector Neu-induced mammary cancer model. Two configurations of this model will be used including one in which ovariectomized rats are given test drugs and the second in which intact rats are treated with tamoxifen and the test drug(s). Drugs to be used include: the monoterpene Perillyl alcohol; the retinoids 9-cis retinoic acid (or Targretin) and 4-HPR; the COX-2 inhibitor Celecoxib; and an EGFR kinase inhibitor. Several of these compounds have been shown to prevent hormonally non-responsive cancer in the rat model proposed. DCIS and carcinoma mammary tissues will be collected from drug-treated and control rats. Differences in gene expression between these tissues will be determined using rat gene expression DNA-chip arrays and rigorous statistical analysis. These differentially expressed genes will be informatically filtered to yield those (approximately 10%) that encode for secreted proteins. Following confirmation of differential gene expression for these selected genes using quantitative-PCR they will be subjected to a proteomic analysis. This analysis will determine if these candidate gene-encoded proteins are differentially expressed in preneoplastic and neoplastic mammary cells of drug treated versus control rats, and whether they are secreted into the blood or mammary ductal fluids in amounts that are modifiable by the drug treatment. Next the human homologues of these rat secreted proteins will be quantified in hormonalty non- responsive breast cancers, breast ductal fluids and sera from patients with various benign, preneoplastic, or neoplastic breast diseases. This project will provide surrogate biomarkers and specific assays for phase II clinical breast cancer prevention trials focused on hormonally non-responsive breast cancer. These surrogate prevention biomarkers, based on proteins that are secreted into blood or breast ductal fluids, will be able to be readily translated into clinical trials in that patient samples for analysis can be collected in a minimally invasive manner.

描述（由申请人提供） 该项目的目的是开发易于翻译的替代生物标志物，用于激素无反应性乳腺癌化学预防试验。为此，将开发替代生物标志物，由可以在血清或乳腺乳头抽吸液中分析的乳腺细胞（肿瘤前，早期肿瘤）分泌的蛋白质组成。这些分泌的蛋白质生物标志物将在大鼠逆转录病毒载体诱导的乳腺癌模型中进行鉴定和验证。将使用该模型的两种构型，其中包括一种卵巢切除大鼠的测试药物，第二种是用他莫昔芬治疗完整大鼠和测试药物（S）。要使用的药物包括：单苯乙烯基醇；类维生素类似于9-CIS视黄酸（或Targretin）和4-HPR； COX-2抑制剂Celecoxib；和EGFR激酶抑制剂。这些化合物中的几种已被证明可预防荷尔蒙非反应性癌症中提出的大鼠模型。 DCIS和癌组织将从药物治疗和对照大鼠中收集。这些组织之间的基因表达差异将使用大鼠基因表达DNA-CHIP阵列和严格的统计分析确定。这些差异表达的基因将被信息过滤，以产生编码分泌蛋白质的基因（约10％）。在使用定量PCR确认这些选定基因的差异基因表达后，将进行蛋白质组学分析。该分析将确定这些候选基因所编码的蛋白是否在药物治疗的药物与对照大鼠的肿瘤和肿瘤乳腺细胞中差异表达，以及它们是否被分泌到血液或乳腺导管液中，以药物治疗可修饰的量。接下来，这些大鼠分泌的蛋白质的人类同源物将在荷尔蒙非反应性乳腺癌，乳腺导管液和血清中进行定量，这些患者的乳腺导管液和血清各种良性，前肿瘤或肿瘤性乳腺癌。该项目将提供替代生物标志物和II期临床乳腺癌预防试验的特定测定法，该试验以荷尔蒙无反应性乳腺癌为例。这些替代的预防生物标志物基于分泌到血液或乳腺导管液中的蛋白质，可以轻松地将其转化为临床试验，因为可以以微创的方式收集患者样品进行分析。