Mouse Models of Human Breast Cancer

这一提议是建立在B.皮尔斯最先提出的假设的基础上的，即“一个确定的干细胞 组织更新所需的是癌症的起源细胞(3)。 乳腺癌临床前小鼠模型的改进可能取决于靶向特定基因的能力 事件对干细胞/祖细胞的影响，这种方法可能会克服 目前可用的乳腺癌小鼠模型。此外，改进的小鼠和人类模型 研究癌前疾病进展的早期步骤是必要的。该提案的基础是 基于在前一个资助时期的几个新的观察：1)P53在激素- 依赖性乳腺进展，2)改变的P53在衰老中的作用，3)产生 携带P53功能获得性突变的小鼠Li-Fraumeni模型4)干/祖细胞的鉴定 乳腺和现有小鼠乳腺癌模型中的细胞标志物5)乳腺癌的发展 有条件地、在某些情况下可逆地激活癌基因或删除抑癌基因的方法 基因。来自四个机构的十名联合调查员小组提供了必要的补充 产生和表征拟议的新的癌症小鼠模型所需的专业知识。以下是 提出的具体目标是：1)建立新的小鼠模型，能够诱导表达分子在 乳腺侧群(SP)细胞，并确定致癌信号通路的影响 SP细胞，以及这些细胞在乳腺肿瘤发生中的需求。2)开发可诱导性 功能评价乳腺SCA-1祖细胞致瘤性的小鼠模型 将反向四环素反应反式激活因子(RTTA)和禽白血病病毒TVA受体导入 SCA-1基因座。3)确定正常乳腺干细胞和祖细胞的细胞谱系标志 腺体和P53缺失的乳腺癌进展模型Balb/c以了解干细胞的作用 细胞在乳腺癌进展和激素依赖和独立乳腺癌的病因学中的作用。 了解P53在乳腺干细胞更新和衰老中的作用。4)发展人 研究早期乳腺癌进展的异种异种移植模型 鼠标中的进程模型。

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 Bcrpl ¿ 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.