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

描述（由申请人提供）：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取得了相当大的进步，但大多数数据来自体外/动物模型或范围有限的群体研究。考虑到miRNA功能的复杂性和乳腺癌的多因素特性，在精心设计的人群研究中，迫切需要系统地研究miRNA在乳腺癌中的作用。在此，我们设计了一个假设驱动的、技术支持的转化项目，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/鉴定具有代表性临床亚型的乳腺癌肿瘤中的乳腺癌失调mirna。我们将采用多种体外实验来表征这些mirna在细胞生长/增殖、分化和癌细胞干性方面的潜力，并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的发现

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.