Telomere induced senescence as a supressor of tumorigenesis

描述(由申请人提供)：人类乳腺癌的发生是由于获得的基因变化使前体癌细胞具有与癌症相关的基因损伤的临界阈值。这种复杂的基因组变化赋予了前体癌细胞无限生长和转移到远处的能力。细胞致瘤潜力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DNA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，从而加剧了基因组的高度不稳定。在完整的P53依赖的DNA损伤反应(DDR)通路的设置下，这种不稳定性促进了细胞衰老，这是一种有效的肿瘤抑制机制。然而，随机丧失P53功能的稀有细胞会进展为癌症。在人类乳腺癌中，端粒功能障碍与从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启动乳腺癌发展的观点。在这项提议中，我们的目标是建立在活体内忠实地概括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，对染色体末端保护是必不可少的。我们最近产生了一只POT1条件性基因敲除小鼠，并表明POT1的缺失会在端粒诱导强大的DNA损伤反应，在没有p53的情况下触发衰老表型。POT1的缺失还会导致广泛的染色体融合，并在P53缺失的情况下发展为癌症。在这项建议中，我们将建立小鼠模型，在P53活性或缺失的情况下，研究端粒功能障碍在乳腺癌发病中的作用，并表征小鼠乳腺肿瘤样本中的染色体异常。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械性的见解。衰老可以抑制乳腺癌的形成，这一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功能的上调很可能有利于激活细胞衰老程序，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.