Role of microRNAs in initiation and progression of breast cancer

描述(申请人提供)：乳腺癌(BRCA)是女性中第二常见的癌症，是一种复杂的、缺乏充分认识的疾病，如果在早期没有发现，往往是致命的。更详细地了解分子机制和调控途径的作用将极大地有助于改进治疗策略的设计和靶点选择。MicroRNAs(MiRNAs)是一种进化保守的、短小的非编码调控RNA，它通过普遍和多功能的机制与其同源的靶mRNAs结合，在转录后调节基因的表达。MiRNAs特定亚群的表达改变与不同类型的血液病和实体瘤有关。使用BRCA临床样本的独立研究已经确定了一小部分miRNAs，这些miRNAs在正常组织和肿瘤组织样本中被区别检测到。因此，这些miRNAs作为BRCA治疗不同方面的新生物标志物的临床价值正在被积极地研究。重要的是，在小鼠模型的细胞系和异种移植模型中的功能分析揭示了其中一些miRNAs的肿瘤抑制和致癌功能。这项建议侧重于将miRNAs作为潜在的肿瘤抑制机制来预防乳腺癌的发生。我们将利用BRCA小鼠模型中的遗传学方法来测试miRNA功能的全球损害增强肿瘤生长和侵袭性的假设。值得注意的是，我们的实验策略将类似于Tyler Jack及其同事成功使用的策略，以揭示miRNAs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系统在乳腺上皮细胞中靶向miRNA加工酶DICER的染色体缺失。将在已建立的BRCA小鼠模型中研究miRNA功能的全球丧失的影响。乳腺限制表达多瘤病毒中T抗原、Neu/HER-2或Wnt-1可导致BRCA具有不同的潜伏期和组织学特征，使人联想到特定的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的使用，用于未来集中于单个miRNA在BRCA中的作用和基于miRNA的治疗策略的开发的研究。与公共卫生相关：microRNAs是最近发现的一类短的非编码RNA基因，它充当基因表达的转录后负调节因子。MicroRNA介导的肿瘤发生调控正成为癌症生物学领域的一个新范式。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，可以很容易地适应常规临床实践，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.