Role of microRNAs in initiation and progression of breast cancer

描述（由申请人提供）：乳腺癌（BrCa）是女性中第二大流行癌症，是一种复杂的、未充分了解的疾病，如果在早期未被发现，通常会致命。更详细地了解分子机制和调控途径的工作将大大有助于改善设计和目标选择的治疗策略。微小RNA（miRNA）是进化上保守的短的非编码调节RNA，其通过经由普遍和通用的机制与其同源靶mRNA结合来转录后调节基因表达。miRNAs的特定亚群的表达改变与不同类型的血液肿瘤和实体瘤有关。使用BrCa临床标本的独立研究已经确定了一小部分miRNA，它们在正常和肿瘤组织标本之间差异检测。因此，这些miRNAs作为BrCa管理不同方面的新型生物标志物的临床价值正在积极研究中。重要的是，在细胞系系统和小鼠模型中的异种移植物移植中的功能分析已经揭示了这些miRNA中的一些的肿瘤抑制和致癌功能。这项提案的重点是miRNA作为潜在的肿瘤抑制机制，以防止乳腺癌的发生。我们将在BrCa的小鼠模型中利用遗传学方法来检验miRNA功能的整体损伤增强肿瘤生长和侵袭性的假设。值得注意的是，我们的实验策略将与泰勒杰克及其同事成功使用的策略相似，以揭示miRNA在K-Ras驱动的肺癌小鼠模型中的肿瘤抑制作用。我们将使用Cre/LoxP系统靶向乳腺上皮中miRNA加工酶Dicer的染色体缺失。将在完善的BrCa小鼠模型中研究miRNA功能的整体丧失的影响。乳腺限制性表达多瘤病毒中T抗原（PyMT）、Neu/HER-2或Wnt-1导致BrCa具有不同的淋巴结和组织学特征，使人联想到特定的人BrCa亚型。我们希望这项提议的结果将揭示miRNAs的病因学贡献，并验证这些小鼠模型在未来研究中的应用，这些研究集中在单个miRNAs在BrCa中的作用和基于miRNAs的治疗策略的开发上。公共卫生相关性：microRNA是近年来发现的一类短的非编码RNA基因，其作为基因表达的转录后负调控因子。microRNA介导的肿瘤发生调节正在成为癌症生物学领域的新范式。我们实施的原位杂交技术提供了其他技术无法超越的miRNA表达的空间分辨率，可以很容易地适应于常规临床实践，以使患者受益并帮助医生做出关键决策。

DESCRIPTION (provided by applicant): Breast carcinoma (BrCa), which is the second most prevalent cancer in women, is a complex, inadequately understood, and often fatal disease when not detected at early stages. A more detailed understanding of the molecular mechanisms and regulatory pathways at work will enormously assist in improving the design and target selection of therapeutic strategies. MicroRNAs (miRNAs) are evolutionary conserved, short non-coding regulatory RNAs that post- transcriptionally modulate gene expression by binding to their cognate target mRNAs via pervasive and versatile mechanisms. Altered expression of specific subsets of miRNAs has been linked to different types of hematologic and solid tumors. Independent studies using BrCa clinical specimens have identified a small subset of miRNAs, which are differentially detected between normal and tumor tissue specimens. Thus, the clinical value of these miRNAs as novel biomarkers for different aspect of BrCa management is being actively investigated. Importantly, functional analyses in cell line systems and xenograft transplantation in mouse models have revealed tumor suppressive and oncogenic functions of some of these miRNAs. This proposal focuses on miRNAs as potential tumor suppressive mechanisms to prevent breast carcinogenesis. We will utilize a genetic approach in mouse models of BrCa to test the hypothesis that global impairment of miRNA functions enhances tumor growth and aggressiveness. Of note, our experimental strategy will be similar to the one successfully used by Tyler Jacks and colleagues to uncover tumor suppressive roles of miRNAs in a K-Ras-driven mouse model of lung cancer. We will target chromosomal deletion of miRNA- processing enzyme Dicer in mammary gland epithelia using the Cre/LoxP system. The effects of global loss of miRNA functions will be studied in well-established mouse models of BrCa. Mammary gland restricted expression of Polyoma virus middle T antigen (PyMT), Neu/HER-2 or Wnt-1 causes BrCa with different latencies and histological features reminiscent of specific human BrCa subtypes. We expect that results of this proposal will uncover an etiological contribution of miRNAs and validate the use of these mouse models for future studies concentrating on the role of individual miRNA in BrCa and development of miRNA-based therapeutic strategies. PUBLIC HEALTH RELEVANCE: MicroRNAs are a recently-discovered class of short non-coding RNA genes, which act as post-transcriptional negative regulators of gene expression. microRNA-mediated regulation of tumorigenesis is emerging as a new paradigm in the field of cancer biology. Our implemented in situ hybridization technology offers spatial resolution of miRNA expression unsurpassed by other techniques, which could be readily adapted to routine clinical practice to benefit patients and assist physicians in making crucial decisions.