Mouse Models of Human Breast Cancer

描述(由申请人提供)： 这一建议是建立在B.皮尔斯首次提出的假设基础上的，即“组织更新所需的特定干细胞是癌症的起源细胞(3)。”我们认为，新的、改进的乳腺癌临床前小鼠模型的开发可能取决于针对干细胞/祖细胞的特定遗传事件的能力，并且这种方法可能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疾病进展的早期步骤。该建议基于在上一个资助期所做的一些新的观察：1)P53在激素依赖的乳腺进展中的作用，2)改变的P53在衰老中的作用，3)产生携带P53功能增强突变的小鼠Li-Fraumeni模型，4)在乳腺和现有的小鼠乳腺癌模型中鉴定干/祖细胞标记5)开发有条件的，在某些情况下可逆地激活癌基因，或删除肿瘤抑制基因的方法。来自四个机构的十名合作研究人员组成的小组提供了必要的和互补的专业知识，以产生和表征拟议的新小鼠癌症模型。1)建立能够诱导Bcrp1+乳腺侧群(SP)细胞分子表达的新的小鼠模型，确定致癌信号通路对SP细胞的影响以及这些细胞在乳腺肿瘤发生中的需求。2)通过将反向四环素反应反式激活因子(RTTA)和禽白血病病毒TVA受体插入Sca-1基因位点，建立一种可诱导的小鼠模型，从功能上评价乳腺Sca-1+祖细胞的致癌作用。3)在正常乳腺和p53缺失的Balb/c乳腺癌进展模型中鉴定干细胞和祖细胞的细胞谱系标记，以了解干细胞在乳腺癌进展中的作用以及激素依赖和非激素依赖性乳腺癌的病因学。了解P53在乳腺干细胞更新和衰老中的作用。4)建立人异种异种移植模型，研究早期乳腺癌的进展情况，并与小鼠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.