Genetic Analysis of the Breast Tumor Microenvironment

描述(申请人提供)：肿瘤间质是肿瘤不可分割的一部分，通过未知的机制重新编程，与上皮性肿瘤细胞共同进化，为肿瘤的启动和发展提供有利的环境。然而，间质的改变是否有助于乳腺癌表型的多样性、异质性和可塑性，以及患者的治疗反应和临床结果尚不清楚。我们使用小鼠模型的联合初步数据表明，Pten和P53通路在乳腺间质成纤维细胞中发挥着关键和独特的肿瘤抑制作用。同时，人类乳腺肿瘤间质的基因表达谱确定了不同的间质亚类，这些亚类可以独立于已建立的临床变量和已建立的分子肿瘤亚型来预测患者的预后。Pten缺失和p53缺失的小鼠成纤维细胞的基因签名与人类肿瘤间质签名的比较表明，小鼠签名存在于人类肿瘤间质中，可以帮助对主要与非管腔乳腺癌相关的间质亚类进行分层，并可以预测不良的患者预后。 这项建议的总体假设是，定义调节肿瘤-间质串扰的途径将导致更好地对乳腺癌患者进行分层，更好地将当前疗法应用于最有可能从中受益的患者，并开发针对我们研究发现的肿瘤-间质相互作用的新疗法。 我们的鼠-人联合方法将利用我们团队开发的新型遗传、基因组和蛋白质组技术来1)揭示间质细胞如何使用整合的转录程序在恶性肿瘤的初始阶段在它们之间以及与肿瘤细胞之间进行通信，2)识别间质表达谱，从而可以更好地对乳腺癌患者进行分层，预测临床结果，并用于基于血清的诊断。这三个项目之间的协同努力，利用鼠标和人类的联合方法，只有由于每个小组提供的独特的专业知识和技术，专注于了解人类乳腺癌中肿瘤-间质对话这一单一任务，并将这些基本信息转化为对间质亚类的分层、预测临床结果和为个别患者开发特定的治疗方法，才是有效的。

DESCRIPTION (provided by applicant): The tumor stroma is an integral part of the tumor that becomes reprogrammed by unknown mechanisms to co-evolve with epithelial tumor cells and provide an environment conducive for tumor initiation and progression. However, whether alterations in the stroma contribute to the diversity, heterogeneity and plasticity of breast cancer phenotypes, and to the therapeutic responses and clinical outcome in patients is unknown. Our combined preliminary data using mouse models suggests that the Pten and p53 pathways play key and distinct tumor suppressor roles in stromal fibroblasts of the mammary gland. In parallel, gene expression profiling of human breast tumor stroma has identified distinct subclasses of stroma that can predict patient outcomes independent of established clinical variables and the established molecular tumor subtypes. Comparison of gene signatures from Pten-null and p53-null mouse fibroblasts to human tumor stroma signatures show that the mouse signatures are present in human tumor stroma, can help stratify stromal subclasses associated with predominantly non-luminal breast cancers, and can predict poor patient outcome. The overall hypothesis for this proposal is that defining the pathways that regulate tumor-stroma crosstalk will lead to better stratification of breast cancer patients, better informed application of current therapies to patients that are most likely to benefit from them, and to the development of new therapies that target the tumor-stromal interactions uncovered by our studies. Our combined mouse-human approach will utilize novel genetic, genomic and proteomic technologies developed by our groups to 1) expose how stromal cells use integrated transcriptional programs to communicate between themselves and with tumor cells during the initial stages of malignancy, and 2) to identify stromal expression profiles that can better stratify breast cancer patients, predict clinical outcome and be used for serum-based diagnostics. The synergistic efforts between the three projects, utilizing a combined mouse-human approach, is only effective because of the unique expertise and technologies provided by each group with a focus on the single task of understanding the tumor-stroma dialogue in human breast cancer, and in translating such basic information to stratify stroma subclasses, predict clinical outcome and develop specific treatments for individual patients.