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

描述(申请人提供)：三阴性乳腺癌(TN，激素受体和HER2阴性)，包括基本和非基本亚型，令人感兴趣，因为它们类似于BRCA1突变携带者的癌症，常见于年轻女性和非裔美国女性。尽管针对DNA损伤反应缺陷的PARP1抑制剂是治疗TN癌症的有希望的药物，但需要针对这些侵袭性癌症的额外治疗靶点。确定TN癌的microRNA(MLR)表达谱将有助于识别改变的信号通路和特定的靶蛋白，从而可能导致合理靶向治疗的发展。由于单个MIR控制多个蛋白质及其信号通路的表达，并给出简单的表达谱，可以对特定肿瘤类型的亚类进行分层，因此MLR表达谱很可能识别TN亚类的亚类，以及可以作为特定亚类的治疗靶点的信号通路。我们建议通过分析TN癌和相关的癌前病变的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表达特征将被用来定义由miR调控的信号通路，这些信号通路在TN癌和前驱病变中显著上调和下调。控制基底和非基底乳腺癌生物学的信号网络将通过4个具体目标来确定：1)365例TN乳腺癌组织芯片(TMA)和RNA制备核心的制备；2)基础和非基础miR图谱的定义，通过原位杂交(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系；3)256例TN乳腺癌和癌前病变TMA的制备；100例基础癌和相关癌前病变的激光捕获显微切割(LCM)后的RNA提取和MLR图谱的确定；4)确定TN癌亚类和癌前病变所特有的miR靶点，利用乳腺癌来源的细胞系确定靶点及其信号通路；操纵miR信号网络以确定乳腺癌细胞系的生物学效应；确定治疗靶点。

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.