Mouse Models of Human Breast Cancer

人类乳腺癌小鼠模型

• 批准号: 7923496
• 负责人: Jeffrey Mark Rosen
• 金额: $ 38.25万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923496
• 关键词: Avian Leukosis Virus; Breast Cancer Model; Carcinoma; Cell Lineage; Cells; Development; Disease; Etiology; Event; Funding; Generations; Genetic; Hormones; Human; Institution; Knock-in Mouse; Malignant Neoplasms; Mammary Tumorigenesis; Mammary gland; Modeling; Mus; Mutation; Oncogenes; Oncogenic; Population; Premalignant; Research Personnel; Role; Side; Signal Pathway; Stem cells; Study models; TP53 gene; Tetracyclines; Tissues; Trans-Activators; Tumor Suppressor Genes; Tva receptor; Xenograft Model; base; gain of function; improved; malignant breast neoplasm; method development; mouse model; novel; pre-clinical; senescence; stem; stem cell division; tumor progression; tumorigenesis

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.

描述（由申请人提供）： 该提议基于B. Pierce首先提出的假设，即“组织更新所需的确定的干细胞是癌的起源细胞（3）。”我们建议开发新的，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茎/祖细胞的能力，并且这种方法可能会克服当前可用的小鼠乳腺癌模型的一些关键局限性。此外，需要改进的小鼠和人类模型，以研究预疾病前疾病进展的早期步骤。 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有条件的方法，在某些情况下可逆地激活癌基因，或删除抑制肿瘤基因。来自四个机构的十个共同投资者组提供了生成和表征拟议的新小鼠癌症模型所需的必要和补充专业知识。提出了以下特定目的：1）生成能够在BCRP1+乳腺侧构群（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 CEIL的影响，以及这些细胞对乳腺肿瘤的需求。 2）开发一种可诱导的小鼠模型，以通过对反向四环素反应反式激活器（RTTA）和Avian Leukosis Virus TVA受体的敲击来评估乳腺SCA-1+祖细胞的肿瘤发生。 3）在正常的乳腺和p53无效的乳腺癌进展模型中鉴定茎和祖细胞的细胞谱系标记，以了解干细胞在乳腺癌进展以及激素依赖性和独立乳腺癌的病因中的作用。 了解p53在乳细胞更新和衰老中的作用。 4）从展开的iobules开发人异种移植模型，以研究早期乳腺癌的进展，以与小鼠中的进展模型进行比较。

项目成果

Use of stem cell markers in dissociated mammary populations.

在分离的乳腺群体中使用干细胞标记。

• DOI: 10.1007/978-1-60761-063-2_3
• 发表时间: 2010
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Shelton,DawneN;Fernandez-Gonzalez,Rodrigo;Illa-Bochaca,Irineu;Ortiz-de-Solorzano,Carlos;Barcellos-Hoff,MaryHelen;Welm,BryanE
• 通讯作者: Welm,BryanE