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 HER2 阴性），包括基础亚型和非基础亚型，令人感兴趣，因为它们类似于 BRCA1 突变携带者的癌症，并且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 癌症的有希望的治疗方法，但这些侵袭性癌症还需要其他治疗靶点。定义 TN 癌症的 microRNA (mlR) 表达谱将能够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开发。由于各个 miR 控制多种蛋白质及其信号通路的表达，并提供可以对特定肿瘤类型的亚类进行分层的简单表达谱，因此 mlR 表达谱很可能会识别 TN 亚型的亚类，以及可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 癌症和相关癌前病变的 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 miR 调节的信号通路，这些信号通路在 TN 癌症和前驱病变中显着上调和下调。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定 miR 与生化和临床特征的关联； 3) 256例TN乳腺癌及癌前病变TMA的制备；激光捕获显微切割 (LCM) 后从 100 种基底癌和相关癌前病变中分离 RNA 并定义 mlR 图谱； 4) 使用乳腺癌来源的细胞系定义 TN 癌症亚类和癌前病变特征的 miR 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.