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

描述（由申请人提供）：三阴性乳腺癌（TN，激素受体和HER 2阴性），包括基础和非基础亚型，是令人感兴趣的，因为它们类似于BRCA 1突变携带者的癌症，并且常见于年轻女性和非洲裔美国女性。尽管靶向缺陷DNA损伤反应的PARP 1抑制剂是TN癌症的有希望的治疗方法，但需要针对这些侵袭性癌症的其他治疗靶点。确定TN癌症的microRNA（mIR）表达谱将允许鉴定改变的信号通路和特异性靶蛋白，这可能导致合理靶向疗法的开发。由于单个miR控制多种蛋白质及其信号通路的表达，并且给出可以将特定肿瘤类型的亚类分层的简单表达谱，因此很可能mIR表达谱将鉴定TN亚型的亚类，以及可以用作特定亚类的治疗靶标的信号通路。我们建议通过分析TN癌和相关癌前病变的miR表达特征来定义驱动TN乳腺癌重要生物学特征的信号通路。miR表达特征将用于定义由miR调节的信号通路，所述miR在TN癌症和前体病变中显著上调和下调。控制TN基底和非基底乳腺癌生物学的信号网络将通过4个具体目标来定义：1）制备365例TN乳腺癌组织微阵列（TMA）和用于RNA制备的核心; 2）基础和非基础miR谱的定义，通过原位杂交（ISH）确认miR的细胞类型表达以及特异性miR与生化和临床特征的关联; 3）制备256例TN乳腺癌和癌前病变TMA;在激光捕获显微切割（LCM）后从100个基底癌和相关癌前病变分离RNA并定义mIR谱; 4）使用乳腺癌衍生的细胞系定义TN癌症亚类和癌前病变特征性的miR的靶标，确认靶标及其信号通路;操纵miR信号网络以确定乳腺癌细胞系中的生物学效应;

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.