Telomere induced senescence as a supressor of tumorigenesis

端粒诱导衰老作为肿瘤发生的抑制因子

基本信息

批准号：
7298033
负责人：
Sandy S Chang
金额：
$ 29.26万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-08 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7298033
关键词：
A Mouse Alleles Apoptosis Benign Binding Biological Assay Biology Breast Breast Carcinoma Candidate Disease Gene Carcinoma Cell Aging Cell Cycle Progression Cell Line Cell Survival Cells Chromosome abnormality Chromosomes Clinical Trials Competence Complex DNA Damage DNA damage checkpoint DNA repair protein Development Dicentric chromosome Disruption Distant Epithelium Event Exposure to Functional disorder Generations Genes Genetic Genome Genomic Hybridizations Genomic Instability Genomics Human Incidence Intraductal Hyperplasia Invasive Knockout Mice Lesion Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Molecular Mus Mutation Neoplasm Metastasis Noninfiltrating Intraductal Carcinoma Pathogenesis Pathway interactions Phenotype Premalignant Recruitment Activity Role Sampling Series Short Tandem Repeat Signal Transduction Single-Stranded Telomere-Binding Proteins Site Spectral Karyotyping TP53 gene Telomere-Binding Proteins Testing Therapeutic Time Tissues Transcriptional Activation Transgenic Mice Tumor Suppressor Proteins Up-Regulation Validation Work cancer cell cohort in vivo insight malignant breast neoplasm mouse model prevent programs recombinase repaired research study response senescence small hairpin RNA telomere tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Human breast cancer arises through the acquisition of genetic changes that endow precursor cancer cells with a critical threshold of cancer-relevant genetic lesions. This complex genomic alterations confer upon precursor cancer cells the ability to grow indefinitely and to metastasize to distant sites. One important mechanism underlying a cell's tumorigenic potential is the status of its telomere. Telomeres are G-rich simple repeat sequences that serve to prevent chromosomal ends from being recognized as DMA double- strand breaks (DSBs). Dysfunctional telomeres resemble DSBs, leading to the formation of dicentric chromosomes that fuel high degrees of genomic instability. In the setting of an intact p53- dependent DNA damage response (DDR) pathway, this instability promotes cellular senescence, a potent tumor suppressor mechanism. However, rare cells that stochastically lose p53 function progress towards cancer. In human breast carcinomas, the observation that telomere dysfunction is associated with the transition from benign ductal hyperplasia to malignant DCIS strongly supports the notion that dysfunctional telomere-driven genomic instability initiates the development of breast cancer. In this proposal, we aim to generate mouse models that faithfully recapitulate human telomere biology in vivo. The telomere binding protein POT1 (protection of telomeres 1) is a single-stranded telomere binding protein that is essential for chromosomal end protection. We recently generated a Pot1 conditional knockout mouse, and show that deletion of Pot1 induces a potent DNA damage response at telomeres that triggers a senescence phenotype in the absence of p53. Deletion of Pot1 also results in extensive chromosomal fusions and progression to cancer in the setting of p53 deficiency. In this proposal we will develop mouse models to examine the role of telomere dysfunction in the pathogenesis of mammary carcinoma in the settings of p53 competence or deficiency and characterize chromosomal aberrations in mouse breast tumor samples. We will also investigate the function of Pot1 loss in human breast cancers. Our proposal should provide mechanistic insights into how the DDR pathway senses dysfunctional telomeres to promote senescence in vivo. The finding that senescence inhibits breast cancer formation could have therapeutic implications. It is likely that up regulation of p53 function by compounds currently undergoing clinical trials would favor the activation of the cellular senescence program, resulting in suppression of breast cancer.

描述（由申请人提供）：人类乳腺癌是通过获得基因改变而产生的，这些基因改变赋予前体癌细胞与癌症相关的基因损伤的临界阈值。这种复杂的基因组改变赋予前体癌细胞无限生长和转移到远处部位的能力。细胞致瘤潜力的一项重要机制是其端粒的状态。端粒是富含 G 的简单重复序列，可防止染色体末端被识别为 DMA 双链断裂 (DSB)。功能失调的端粒类似于 DSB，导致双着丝粒染色体的形成，从而加剧基因组的高度不稳定。在完整的 p53 依赖性 DNA 损伤反应 (DDR) 途径的情况下，这种不稳定性会促进细胞衰老，这是一种有效的肿瘤抑制机制。然而，随机失去 p53 功能的罕见细胞会发展为癌症。在人类乳腺癌中，观察到端粒功能障碍与良性导管增生到恶性 DCIS 的转变相关，这有力地支持了功能失调的端粒驱动的基因组不稳定性引发乳腺癌的发展这一观点。在这项提案中，我们的目标是生成能够忠实再现体内人类端粒生物学的小鼠模型。端粒结合蛋白 POT1（端粒保护 1）是一种单链端粒结合蛋白，对于染色体末端保护至关重要。我们最近培育了 Pot1 条件敲除小鼠，并表明 Pot1 的缺失会在端粒处诱导有效的 DNA 损伤反应，从而在 p53 缺失的情况下触发衰老表型。 Pot1 缺失还会导致广泛的染色体融合，并在 p53 缺陷的情况下进展为癌症。在本提案中，我们将开发小鼠模型来检查端粒功能障碍在 p53 功能或缺陷的情况下乳腺癌发病机制中的作用，并表征小鼠乳腺肿瘤样本中的染色体畸变。我们还将研究 Pot1 缺失在人类乳腺癌中的功能。我们的建议应该提供关于 DDR 通路如何感知功能失调的端粒以促进体内衰老的机制见解。衰老抑制乳腺癌形成的发现可能具有治疗意义。目前正在进行临床试验的化合物对 p53 功能的上调可能有利于细胞衰老程序的激活，从而抑制乳腺癌。