Conditional Knockdown Mouse Models for Mammary Tumorigenesis

乳腺肿瘤发生的条件敲除小鼠模型

• 批准号: 8399985
• 负责人: Roberto Droz-Rosario
• 金额: $ 2.24万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399985
• 关键词: Address; Animal Cancer Model; BRCA2 gene; Cancerous; Cells; Clinic; Control Animal; DNA Damage; DNA Repair; Data; Defect; Development; Diagnosis; Disease; Down-Regulation; Epithelial Cells; Etiology; Event; Foundations; Functional disorder; Genes; Genome; Genome Stability; Genomic Instability; Goals; Growth; Human; In Vitro; Lead; Lesion; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Molecular; Molecular Profiling; Monitor; Mus; Mutation; Myoepithelial cell; Patients; Phase; Play; Proteins; Radiation; Reporting; Research; Resolution; Risk; Role; Sampling; Site; Testing; Tissues; Training; Transactivation; Transgenic Mice; Tumor Suppressor Genes; Work; base; cancer diagnosis; cancer type; cell type; in vivo; irradiation; malignant breast neoplasm; mouse model; response; triple-negative invasive breast carcinoma; tumorigenesis

DESCRIPTION (provided by applicant): Breast cancer represents a significant portion of the new cancer diagnosis reported yearly. To understand how different breast cancers types arise, we need to identify additional etiological factors for mammary tumorigenesis. In a preliminary study of human breast tumor samples, BCCIP levels were abnormal in approximately 33% of the cases, including 45% among Triple Negative Breast Cancer (TNBC) and 25% among in non- TNBC. We hypothesize that BCCIP defects in mammary tissue contribute to tumorigenesis, particularly of sporadic TNBC. To test the hypothesis I proposed to use a Cre-LoxP mediated BCCIP conditional knockdown in specific cell types of the mouse mammary gland. Preliminary data of this study suggest BCCIP downregulation in myoepithelial cells causes development of discrete lesions. Such growth has not been observed in the control animals. For the following phase of my training, I propose three aims to further test the hypothesis and address the etiological roles of BCCIP deficiency in mammary tumorigenesis. Aim 1 will detect and molecularly characterize the spontaneous breast cancer formed in BCCIP deficient mice to test the hypothesis that BCCIP deficiency preferably causes triple negative cancer. Aim 2 will use radiation induced breast cancer in the BCCIP deficient mouse model to test the hypothesis that BCCIP plays a role in DNA damage induced breast cancer, and to identify the role of BCCIP in mammary response to DNA damage. Aim 3 will use in vitro and in vivo approaches to understand the mechanisms by which BCCIP deficiency contribute to genomic instability in the mammary epithelial cells. PUBLIC HEALTH RELEVANCE: The molecular etiology of breast cancer has been not been fully elucidated. Based on a preliminary study with more than 400 cases, ~1/3 of the breast cancers lost BCCIP expression, including 49% of the triple negative breast cancer. This study will generate a transgenic mouse model to address the mechanisms by which BCCIP deficiency contributes development of breast cancer. Completion of the study will help us to understand events that lead to cancer and potentially contribute to develop better ways to appropriately diagnose, and treat patients according to the molecular profile of their disease.

描述(申请人提供)：乳腺癌占每年报告的新癌症诊断的很大一部分。为了了解不同类型的乳腺癌是如何发生的，我们需要确定乳腺肿瘤发生的其他病因。在对人类乳腺肿瘤样本的初步研究中，大约33%的病例BCCIP水平异常，其中45%在三阴性乳腺癌(TNBC)中，25%在非TNBC中。我们假设乳腺组织中的BCCIP缺陷有助于肿瘤的发生，特别是散发性TNBC。为了验证这一假设，我提议在小鼠乳腺的特定细胞类型中使用Cre-loxP介导的BCCIP条件敲除。这项研究的初步数据表明，BCCIP下调肌上皮细胞的表达导致了离散病变的发生。在对照动物身上没有观察到这样的生长。在接下来的培训阶段，我提出了三个目标，以进一步检验这一假设，并解决BCCIP缺陷在乳腺肿瘤发生中的病因学作用。目的1对BCCIP基因缺陷小鼠所形成的自发性乳腺癌进行检测和分子特征分析，以验证BCCIP缺陷可能导致三重阴性癌症的假说。目的2以BCCIP基因缺陷小鼠为模型，验证BCCIP在DNA损伤诱发乳腺癌中的作用，探讨BCCIP在乳腺DNA损伤反应中的作用。目的3将使用体外和体内方法来了解BCCIP缺陷导致乳腺上皮细胞基因组不稳定的机制。 公共卫生相关性：乳腺癌的分子病因学尚未完全阐明。根据对400多例乳腺癌的初步研究，~1/3的乳腺癌BCCIP表达缺失，包括49%的三阴性乳腺癌。这项研究将建立转基因小鼠模型，以探讨BCCIP缺陷促进乳腺癌发生的机制。这项研究的完成将有助于我们了解导致癌症的事件，并可能有助于开发更好的方法，根据患者的疾病分子特征适当地诊断和治疗患者。