Mouse Models of Human Breast Cancer

描述（由申请人提供）： 这个建议是以B首先提出的假设为前提的。Pierce说：“组织更新所需的确定的干细胞是癌的起源细胞（3）。“我们提出，开发新的，改进的乳腺癌临床前小鼠模型可能取决于将特定遗传事件靶向干/祖细胞的能力，这种方法可以克服目前可用的乳腺癌小鼠模型的一些关键限制。此外，需要改进的小鼠和人类模型来研究癌前病变进展的早期步骤。该提案是基于上一个供资期间提出的若干新的意见：1）p53在乳腺癌依赖性乳腺进展中的作用，2）改变的p53在衰老中的作用，3）产生携带功能获得性p53突变的小鼠Li-Fraumeni模型，4）乳腺和现有小鼠乳腺癌模型中干/祖细胞标志物的鉴定5）开发有条件地，并且在某些情况下可逆地激活癌基因的方法，或删除肿瘤抑制基因。来自四个机构的十名共同研究者提供了必要的和互补的专业知识，以生成和表征所提出的新的小鼠癌症模型。1）建立能在Bcrp 1+乳腺侧群（SP）细胞中诱导表达分子的新小鼠模型，并确定致癌信号通路对SP细胞的影响，以及这些细胞对乳腺肿瘤发生的需求。2)通过将反向四环素应答反式激活因子（rtTA）和禽白血病病毒TVA受体敲入Sca-1基因座，开发一种诱导型小鼠模型，以功能性评估乳腺Sca-1+祖细胞中的肿瘤发生。3)鉴定正常乳腺和乳腺癌进展的p53无效Balb/c模型中干细胞和祖细胞的细胞谱系标志物，以了解干细胞在乳腺癌进展中的作用以及在乳腺癌依赖性和非依赖性乳腺癌病因学中的作用。 了解p53在乳腺干细胞更新和衰老中的作用。4)从未折叠的小叶建立人异种移植模型，以研究早期乳腺癌进展，并与小鼠中的进展模型进行比较。

DESCRIPTION (provided by applicant): This proposal is predicated on the hypothesis first proposed by B. Pierce that "a determined stem cell required for tissue renewal is the cell of origin for carcinomas (3)." We propose that the development of new, improved preclinical mouse models for breast cancer may depend on the ability to target specific genetic events to stem/progenitor cells, and that this approach may overcome some of the key limitations of currently available mouse models of breast cancer. Furthermore, improved mouse and human models for studying the early steps in the progression of premalignant disease are required. The proposal is based upon several novel observations made during the previous funding period: 1) the role of p53 in hormone-dependent mammary gland progression, 2) the role of altered p53 in senescence, 3) the generation of a mouse Li-Fraumeni model carrying a gain-of-function p53 mutation, 4) the identification of stem/progenitor cell markers in the mammary gland and existing mouse breast cancer models 5) the development of methods to conditionally, and in some cases reversibly activate oncogenes, or delete tumor suppressor genes. The group of ten co-investigators from four institutions provides the necessary and complementary expertise required to generate and characterize the proposed new mouse models of cancer. The following specific aims are proposed: 1) To generate new mouse models capable of inducibly expressing molecules in Bcrp1+ mammary side-population (SP) cells, and to determine the impact of oncogenic signaling pathways on SP ceils, and the requirement of these cells for mammary tumorigenesis. 2) To develop an inducible mouse model to functionally assess oncogenesis in mammary gland Sca-1+ progenitor cells by a knock-in of the reverse tetracycline-responsive transactivator (rtTA) and the avian leukosis virus TVA receptor into the Sca-1 locus. 3) To identify cell lineage markers for stem and progenitor cells in both the normal mammary gland and the p53 null Balb/c model of breast cancer progression in order to understand the role of stem cells in breast cancer progression and in the etiology of hormone-dependent and independent breast cancer. To understand the role of p53 in mammary stem cell renewal and senescence. 4) To develop a human xenograft model from unfolded Iobules to study early breast cancer progression for comparison with the progression models in the mouse.