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遗传变化而产生的，这些遗传变化赋予前体癌细胞癌症相关遗传病变的临界阈值。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，其用于防止染色体末端被识别为DNA双链断裂（DSB）。功能异常的端粒类似于DSB，导致形成双着丝粒染色体，从而导致基因组高度不稳定。在一个完整的p53依赖性DNA损伤反应（DDR）途径的设置中，这种不稳定性促进细胞衰老，一种有效的肿瘤抑制机制。然而，随机失去p53功能的罕见细胞向癌症发展。在人类乳腺癌中，端粒功能障碍与从良性导管增生到恶性DCIS的转变相关的观察结果强烈支持功能障碍的端粒驱动的基因组不稳定性引发乳腺癌发展的观点。在这个建议中，我们的目标是产生小鼠模型，忠实地重演人类端粒生物学在体内。端粒结合蛋白POT1（protection of telomeres 1）是一种单链端粒结合蛋白，对染色体末端保护至关重要。我们最近产生了一个Pot1条件性基因敲除小鼠，并表明Pot1的缺失诱导了一个有效的DNA损伤反应，在端粒，触发衰老表型在p53的情况下。Pot1的缺失也导致广泛的染色体融合和p53缺陷背景下的癌症进展。在这个建议中，我们将开发小鼠模型，研究端粒功能障碍在乳腺癌的发病机制中的作用，在设置的p53的能力或缺陷，并在小鼠乳腺肿瘤样本的染色体畸变的特点。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机制的见解，DDR途径的感官功能失调的端粒，以促进体内衰老。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上调p53功能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.