Program Project in Models of Breast Cancer

描述（由申请人提供）：本计划项目拨款申请包括五个互动实验室项目和两个核心，致力于通过研究小鼠模型来取得人类乳腺癌的进展。通过共享现有菌株，合作开发新菌株，设计和使用成像核心，发现和应用基因分型和表型的新方法，以及使用p01开发的试剂在小鼠中进行治疗试验，实现了协同和经济的努力。活跃的P01癌症临床医生致力于确保对临床思维、教育和研究产生有意义的影响。项目1侧重于与乳腺癌形成和进展有关的基因，在体内和体外将基于禽类逆转录病毒载体的基因传递到乳腺细胞。项目2描述了TGF缺失的影响。研究了在转移性乳腺癌细胞中的肿瘤抑制功能，并研究了介导小鼠和人肺转移的肺转移基因表达特征，包括Id基因。项目3将利用Hsp90抑制剂和PI3K、AKt选择性抑制剂，确定PI3K/AKt信号通路在癌症中的作用，并继续探索Hsp90与HER2的联合调控，目前已取得临床进展。项目4将描述发生在hdr缺陷乳腺上皮中的乳腺肿瘤及其肺转移。它将在不同的小鼠模型中评估遗传不稳定性，以确定正常、修复缺陷和癌基因诱导的乳腺上皮的DNA损伤反应。项目5将研究小鼠乳腺上皮细胞和癌症上皮细胞中条件id家族过表达对肿瘤发生、进展和转移的影响，这些细胞来自几个明确定义的遗传背景。在与其他项目的合作中，它将检查id1变异模型的肿瘤启动和转移特性，并继续开发治疗药物。成像核心为这些项目提供先进的成像技术。Larry Norton和Joan Massague担任项目主任和联合主任，

DESCRIPTION (provided by applicant): This Program Project Grant application presents five interactive laboratory projects and two cores dedicated to making progress against human breast cancer by studying mouse models. It achieves synergy and an economy of effort by sharing existing strains, collaboratively developing new strains, designing and using an Imaging Core, discovering and applying new methods for genotyping and phenotyping, and the execution of therapeutic trials in mice using P01-developed reagents. Active cancer clinicians in the P01 are committed to assuring a meaningful impact on clinical thinking, education, and research. Project 1 focuses on the genes implicated in mammary cancer formation and progression, applying avian retroviral vector-based delivery of genes to mammary cells in vivo and iin vitro. Project 2 delineates the effects of the loss of TGF.'s tumor-suppressive function in metastatic breast cancer cells and studies a lung metastasis gene expression signature, including Id genes, that mediates pulmonary metastasis in mouse and human. Project 3 will use Hsp90 inhibitors and selective inhibitors of PI3K and AKt to determine the role of PI3K/AKt signaling in cancer, and continue to explore joint Hsp90 and HER2 modulation, which has already led to a clinical advance. Project 4 will characterize mammary tumors and their lung metastases occurring in HDR-deficient mammary epithelium. It will evaluate genetic instability in diverse mouse models to define the DNA damage response in normal, repair-deficient and oncogene-induced mammary epithelium. Project 5 will examine the effects on tumor initiation, progression, and metastasis of conditional Id-family over-expression in murine mammary epithelial cells and cancer epithelial cells arising from several well-defined genetic backgrounds. In collaboration with other projects it will examine the tumor-initiating and metastatic properties of Id1-variant models, and continue to develop therapeutic agents. The Imaging Core supplies advanced imaging technology to these projects. Larry Norton and Joan Massague serve as Program Director and Co-Director, and a Leadership Core will offer expertise in molecular array technology and biostatistics.