Project 4

项目4在揭示microRNAs在人类癌症中扮演的各种角色方面发挥了带头作用。我们会 在此基础上，增加对乳腺癌的生物学关注。我们将从正常的处女和分娩的雌性小鼠中分离出六种明确的乳腺上皮细胞类型，并定义它们的miRNA和mRNA表达谱。通过这样做，我们希望更好地定义乳腺干细胞(MASC)，并了解维持其自我更新的途径。这将包括对MASC中重要的miRNAs和miRNA靶标的定义。以正常细胞为参照点，我们将致力于了解乳腺肿瘤起始细胞与正常乳腺干细胞的关系。在一定程度上，我们的目标是测试肿瘤起始群体的相关性，到目前为止，这些群体只在移植研究中被检测到，与乳腺癌基础肿瘤发生的活体模型有关。我们希望确定决定肿瘤启动潜力的途径，并将这些途径与乳腺干细胞使用的自我更新途径联系起来。我们理解正常细胞和肿瘤细胞都在上下文中发挥作用，因此我们将努力了解体内利基环境如何支持MASC自我更新。类似地，我们会问，肿瘤启动细胞是否占据了一席之地，或者它们的特殊地位是否是细胞自主属性。随着意识到通常是转移性疾病导致患者死亡，我们也将探索播散性肿瘤细胞所占据的利基市场，这些细胞可能在最初的治疗后休眠数十年，然后发展为坦率的转移。使用一系列高度创新的策略，包括分子图谱、基于RNAi的遗传学和复杂的整体成像，该项目采取了一种全面的方法来了解miRNAs在乳腺癌中的作用。

Project 4 has been a leader in revealing the myriad roles played by microRNAs in human cancer. We will build upon this foundation with an increased biological focus on breast cancer. We will isolate the six, well defined mammary epithelial cell types from normal virgin and parous female mice and define their miRNA and mRNA expression profiles. In so doing, we hope to better define the mammary stem cell (MaSC) and gain an appreciation for the pathways that maintain its self-renewal. This will include a definition of miRNAs and miRNA targets that are important in the MaSC. Using normal cells as a reference point, we will work to understand the relafionship between mammary tumor initiating cells and normal mammary stem cells. In part, we aim to test the relevance of tumor initiating populations, which thus far have only been detected in transplantation studies, to breast cancer in in vivo models of basal tumorigenesis. We hope to identify pathways that determine tumor initiating potential and to relate these to self-renewal pathways used by mammary stem cells. We appreciate that both normal and tumor cells function in context, and we will therefore strive to understand how the in vivo niche supports MaSC self-renewal. Similarly, we will ask whether tumor initiating cells occupy a niche or whether their special status is a cell autonomous property. With the realization that it is usually metastatic disease that kills patients, we will also probe the niches occupied by disseminated tumor cells, which can lie dormant for decades following initial treatment before they progress to frank metastases. Using a series of highly innovative strategies, including molecular profiling, RNAi-based genetics, and sophisticated imaging a whole, this Project takes a comprehensive approach to understanding the roles of miRNAs in breast cancer.