MicroRNA & Breast Cancer: Functional Characterization in a Population-Based Study

描述(申请人提供)：尽管我们对microRNA(MiRNA)在与癌症相关的基本细胞过程中的重要作用的了解有了很大的进步，但大多数数据来自有限范围的体外/动物模型或种群研究。在考虑到miRNA功能的复杂性和乳腺癌的多因素性质的精心设计的人群研究中，迫切需要对miRNA在乳腺癌中的作用进行系统的研究。在这里，我们设计了一个假设驱动的、技术使能的翻译项目，旨在系统地阐明miRNA在乳腺癌生存中的作用。利用癌症基因组图谱(TCGA)的最新结果和我们改进的深度测序方法，我们将验证/识别具有代表性临床亚型的乳腺肿瘤中调控异常的乳腺癌miRNAs。我们将使用多个体外实验来鉴定这些miRNAs在细胞生长/增殖、分化和癌细胞干细胞方面的潜力，以及确定它们在乳腺细胞系中的下游靶点。然后，我们将独立验证实验室在 一项以人群为基础的流行病学研究，长岛乳腺癌研究项目(LIBCSP)。拟议研究的独特优势是我们能够将最新的基因组技术(深度测序)、功能分子方法(体外分析)与经典流行病学(基于人群的研究)相结合，在功能分子方法中可以表征候选miRNAs的表型相关性，在经典流行病学中可以考虑复杂的外源因素和患者信息。这种多尺度、多学科和多方向的方法可以更好地描述miRNA与乳腺癌发生和进展之间的因果关系。该项目具有确定预测乳腺癌结果的miRNA签名的真正潜力。

DESCRIPTION (provided by applicant): Despite considerable advancement in our knowledge about the significant role of microRNA (miRNA) in fundamental cellular processes related to cancer, most data come from in vitro/animal models or population studies with limited scope. There is a critical need for systematic investigation on the role of miRNA in breast cancer in well-designed population studies that take into account the complexity of miRNA functions and multifactorial nature of breast cancer. Herein, we have designed a hypothesis-driven, technology-enabled translational project aimed at systematically elucidating the role of miRNA in breast cancer survival. Taking advantage of the latest results from the Cancer Genome Atlas (TCGA) and our improved deep sequencing method, we will validate/identify breast cancer dysregulated miRNAs in breast tumors of representative clinical subtypes. We will employ multiple in vitro assays to characterize these miRNAs for their potential in cell growth/proliferation, differentiation, and cancer cell stemness, as well as to identify their down-stream targets in breast cell lines. We will then independently validate the laboratory findings in a population-based epidemiologic study, the Long Island Breast Cancer Study Project (LIBCSP). The unique strength of the proposed study is our ability to incorporate latest genomic technology (deep sequencing), functional molecular methods (in vitro assays), in which phenotypic relevance of candidate miRNAs can be characterized, with classic epidemiology (population-based study), in which complex exogenous factors and patient information can be taken into account. This multi-scale, multi-disciplinary, and multi-directional approach allows a better characterization of the causal relationship between miRNA and breast cancer development and progression. This project has the real potential to identify a miRNA signature that predicts breast cancer outcomes.