MicroRNA profiles of TN breast cancer to define subgroups and targets for therapy

TN 乳腺癌的 MicroRNA 图谱可定义亚组和治疗靶点

基本信息

批准号：
8207324
负责人：
KAY HUEBNER
金额：
$ 46.51万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8207324
关键词：
African American Automobile Driving Behavior Biochemical Bioinformatics Biological Biological Assay Biology Breast Cancer Cell Cancer cell line Cell Line Characteristics Clinical Clinical Data Clinical Treatment Cluster Analysis DNA Damage Data Data Files Databases Development ERBB2 gene Exhibits Gene Targeting Hormone Receptor In Situ Hybridization In Vitro Individual Informatics Lead Lesion Link Malignant Neoplasms MicroRNAs Mining Molecular Profiling Normal tissue morphology Paraffin Premalignant Preparation Prevention Principal Investigator Proteins RNA Signal Pathway Signal Transduction Specificity Subgroup System Tissue Microarray Tissues Treatment outcome Tumor Tissue Woman cell type digital in vitro Model inhibitor/antagonist interest laser capture microdissection link protein malignant breast neoplasm mutation carrier programs protein expression response therapeutic target triple-negative invasive breast carcinoma tumor

项目摘要

DESCRIPTION (provided by applicant): Triple negative breast cancers (TN, negative for hormone receptors and HER2), which include basal and non-basal subtypes, are of interest because they resemble cancers of BRCAl mutation carriers and are frequent in young women and African-American women. Although PARP1 inhibitors, targeting defective DNA damage responses, are promising treatments for TN cancers, additional therapeutic targets for these aggressive cancers are needed. Defining the microRNA (mlR) expression profiles of TN cancers will allow identification of altered signal pathways and specific target proteins that may lead to development of rationally targeted therapies. Because individual miRs control expression of multiple proteins and their signal pathways, and give simple expression profiles that can stratify subclasses of specific tumor types, it is likely that mlR expression profiles will identify subclasses of the TN subtype, and signal pathways that could serve as therapeutic targets for specific subclasses. We propose to define the signal pathways driving important biological features of TN breast cancers by profiling miR expression signatures of TN cancers and associated premalignant lesions. The miR expression signatures will be used to define signal pathways regulated by miRs that are significantly up and down-modulated in TN cancers and precursor lesions. Signaling networks that control the biology of TN basal and non-basal breast cancers will be defined through 4 specific aims: 1) preparation of 365 case TN breast cancer tissue microarray (TMA) and cores for RNA preparation; 2) definition of basal and non-basal miR profiles, confirmation of cell type expression of miRs by in situ hybridization (ISH) and association of specific miRs with biochemical and clinical features; 3) preparation of a 256 case TN breast cancer and premalignant lesion TMA; RNA isolation from 100 basal cancers and associated premalignant lesions after laser capture microdissection (LCM) and definition of mlR profiles; 4) definition of targets of miRs characteristic of TN cancer subclasses and premalignant lesions, confirmation of targets and their signal pathways, using breast cancer-derived cell lines; manipulation of the miR signal networks to determine biological effects in breast cancer cell lines; Identify therapeutic targets.

描述（由申请人提供）：包括基础和非基质亚型在内的三重阴性乳腺癌（TN，激素受体阴性和HER2）引起了人们的关注，因为它们类似于Brcal突变载体的癌症，并且在年轻女性和非裔美国妇女中经常出现。尽管PARP1抑制剂（靶向有缺陷的DNA损伤反应）是TN癌症的有前途的治疗方法，但需要针对这些侵略性癌症的其他治疗靶标。定义TN癌症的microRNA（MLR）表达谱将允许鉴定信号途径改变的信号途径和特定靶蛋白，这些蛋白可能导致理性靶向疗法的发展。由于各个miR控制多种蛋白质及其信号途径的表达，并提供可以对特定肿瘤类型进行分层亚类的简单表达曲线，因此MLR表达曲线可能会鉴定TN亚型的亚类，以及可以用作特定子类的治疗靶标的信号途径。我们建议通过分析TN癌和相关前病变的miR表达特征来定义驱动TN乳腺癌重要生物学特征的信号途径。 MIR表达特征将用于定义由MIR调节的信号途径，这些MIR在TN癌症和前体病变中显着上下调节。控制TN基底和非基质乳腺癌生物学的信号网络将通过4个特定目的来定义：1）制备365例TN乳腺癌组织微阵列（TMA）和核心进行RNA准备； 2）基础和非基础miR谱的定义，通过原位杂交（ISH）（ISH）确认MIR的细胞类型表达以及特定miR与生化和临床特征的关联； 3）制备256例TN乳腺癌和预先病变的病变TMA；激光捕获显微解剖（LCM）和MLR谱的定义后，从100个基底癌和相关前病变中的RNA分离； 4）使用乳腺癌衍生的细胞系，对TN癌亚类和预触发病变的MIR靶标的定义，靶标及其信号途径的确认；操纵miR信号网络以确定乳腺癌细胞系中的生物学作用；确定治疗靶标。