Telomere induced senescence as a supressor of tumorigenesis

描述（由申请人提供）：人类乳腺癌是通过获得基因变化而产生的，这些基因变化使前体癌细胞具有与癌症相关的遗传病变的临界阈值。这种复杂的基因组改变赋予了前体癌细胞无限生长和转移到远处的能力。细胞致瘤潜能的一个重要机制是其端粒的状态。端粒是富含g的简单重复序列，用于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，导致双中心染色体的形成，从而加剧了基因组的高度不稳定性。在完整的p53依赖的DNA损伤反应（DDR）通路中，这种不稳定性促进细胞衰老，这是一种有效的肿瘤抑制机制。然而，随机丧失p53功能的罕见细胞会发展成癌症。在人类乳腺癌中，端粒功能障碍与良性导管增生向恶性DCIS的转变有关，这一观察结果有力地支持了端粒功能障碍驱动的基因组不稳定性启动乳腺癌发展的观点。在本提案中，我们的目标是生成忠实地再现人类端粒生物学的小鼠模型。端粒结合蛋白POT1（保护端粒1）是一种单链端粒结合蛋白，对染色体末端保护至关重要。我们最近培育了一只Pot1条件敲除小鼠，并表明Pot1的缺失在端粒处诱导了强有力的DNA损伤反应，从而在p53缺失的情况下引发衰老表型。在p53缺乏的情况下，Pot1的缺失也会导致广泛的染色体融合和癌症的进展。在本提案中，我们将开发小鼠模型，在p53能力或缺乏的情况下检查端粒功能障碍在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作用。我们的建议应该为DDR途径如何感知功能失调的端粒以促进体内衰老提供机制见解。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。

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.