Genetic Analysis of the Breast Tumor Microenvironment

描述(由申请人提供) 微环境在肿瘤进展中的作用是一个新兴的研究领域，显然对人类癌症的诊断和治疗具有重要的临床意义。正常上皮细胞向转移性肿瘤细胞的转化被认为是一个多阶段的过程，需要上皮肿瘤细胞内进行性的遗传改变，一直是密集研究的焦点。然而，肿瘤微环境中的许多其他类型的细胞越来越被认为是复杂生物网络的组成部分，类似于器官系统，对肿瘤的进展至关重要。这个项目的成员将使用人类遗传方法和小鼠遗传模型来研究基因 肿瘤微环境中两种细胞类型的作用：肿瘤间质成纤维细胞和巨噬细胞。该计划由四个核心支持的三个互动项目组成。项目1将使用人类基因方法和激光捕获显微解剖来分析发生在人类乳腺癌样本间质间质中的基因变化。项目1、2和3将开发和使用小鼠模型来实验性地测试三种遗传途径：PTEN、Rb/E2F和ras/ETS-2在肿瘤微环境中的作用。这项工作将得到转基因/基因敲除核心、小鼠病理学核心、研究方法和生物统计学核心以及管理核心的支持。该计划的主要近期目标是：1)在全基因组范围内识别发生在乳腺肿瘤中的基因改变。 从人类乳腺肿瘤样本中分离出间质细胞，以及在乳腺肿瘤间质中发现的基因变化与乳腺癌患者临床预后的相关性；2)实验验证来自乳腺间质细胞的基因作用在乳腺肿瘤进展中的重要作用。这包括建立小鼠模型，允许测试微环境细胞中的基因作用，并且应该在基因水平上更准确地反映人类乳腺肿瘤的进展。该计划的长期目标是利用我们对肿瘤微环境在乳腺癌进展中的作用的加深了解所获得的信息，来改进诊断、预后和治疗的策略。 人类乳腺癌的治疗。

DESCRIPTION (provided by applicant) The role of the microenvironment in tumor progression is an emerging area of research that clearly has important clinical implications, both for diagnosis and treatment of human carcinoma. The conversion of normal epithelial cells to metastatic tumor cells is accepted as a multi-stage process that requires progressive genetic alterations within the epithelial tumor cell and has been the focus of intense investigation. However, the many other cell types in the tumor microenvironment are increasingly appreciated as components of a complex biological network, akin to an organ system, that are critical for tumor progression. The members of this Program Project Grant will use both human genetic approaches and mouse genetic models to study gene action from two cell types in the tumor microenvironment: tumor stromal fibroblasts and macrophages. The program consists of three interactive Projects supported by four Cores. Project 1 will use human genetic approaches and laser capture microdissection to analyze genetic alterations that occur in the stromal compartment of human breast cancer samples. Projects 1, 2 and 3 will develop and use mouse models to experimentally test the role of three genetic pathways: Pten, Rb/E2F and ras/ets-2 in the tumor microenvironment. This work will be supported by the Transgenic/Knockout Core, the Mouse Pathology Core, the Research Methods and Biostatistics Core and the Administrative Core. The major, immediate goals of this program are: 1) identification on a genome-wide scale of genetic alterations that occur in mammary tumor stromal cells isolated from human mammary tumor samples and the correlation of genetic changes found in mammary tumor stroma with clinical outcome of breast cancer patients; 2) experimental verification of the essential role of gene action from mammary stromal cells during mammary tumor progression. This involves creation of mouse models that allow gene action in cells of the microenvironment to be tested and that should more accurately reflect mammary tumor progression in humans at the genetic level. The long-term goal of this Program is to use the information gained from our increased understanding of the role of the tumor microenvironment in breast cancer progress to improve strategies for the diagnosis, prognostication and treatment of human breast cancer.