Gain of function mutant p53 in telomere uncapping-driven breast tumorigenesis

描述（由申请方提供）：人散发性乳腺癌的特征是存在复杂的细胞遗传学畸变。这种复杂性是乳腺癌研究人员开发实验模型系统以确定乳腺肿瘤发展的分子遗传病因学的最重要挑战之一。我们的长期目标是建立“染色体不稳定性”小鼠乳腺癌模型，重现高度重排和突变的人类乳腺癌基因组的显著特征，并发现体内乳腺癌发生中涉及的“因果”基因组事件。导致乳腺癌基因组不稳定的一个重要机制是端粒功能障碍，端粒是染色体的物理末端，可以保护天然染色体末端不被识别为受损的DNA，并抑制不适当的DNA修复。另一方面，最近在人类乳腺癌的系统基因组分析显示，肿瘤抑制基因p53是最常见的警报基因，主要是通过错义突变，导致突变p53蛋白的积累，获得致癌功能的获得。为了忠实地类似于在人乳腺癌中观察到的这两个重要特征，染色体不稳定性和功能获得性突变体p53的表达，我们已经设计了一种新的小鼠乳腺癌模型，该模型具有功能失调的端粒诱导的染色体不稳定性和乳腺上皮中“热点”功能获得性突变体p53的表达。我们的初步结果表明，端粒脱帽导致功能失调的端粒激活DNA损伤反应（DDR）介导的凋亡途径，以抑制染色体不稳定性驱动的肿瘤发生在没有p53，而“热点”突变体p53抑制端粒脱帽诱导的细胞死亡，促进细胞转化。此外，我们观察到突变型p53与乳腺上皮中功能失调的端粒合作，促进肿瘤进展为体内浸润性乳腺癌。在本申请中，我们将测试我们的假设，即功能获得性突变体p53抑制端粒脱帽诱导的DDR介导的细胞凋亡，以增强体内染色体不稳定性驱动的乳腺癌发生。这两个具体目标旨在检验这一假设。在目标1中，我们将产生小鼠模型来测试功能获得性突变体p53与端粒脱帽启动的染色体不稳定性合作以促进体内乳腺癌发生的可能性。在目标2中，我们将研究功能获得性突变p53促进染色体不稳定性驱动的乳腺肿瘤发展的分子机制。我们预计，我们的工程染色体不稳定小鼠模型将忠实地再现人类乳腺癌的复杂细胞遗传学畸变，并帮助我们确定新的分子靶点，以改善预防和治疗乳腺癌的策略。

DESCRIPTION (provided by applicant): Human sporadic breast carcinomas are characterized by the presence of complex cytogenetic aberrations. This complexity represents one of the foremost challenges for breast cancer researchers developing the experimental model systems to identify the molecular genetic etiology of breast tumor development. Our long term goal is to establish "chromosomal instability" mouse breast cancer models that recapitulate the salient features of highly rearranged and mutated human breast cancer genomes and discover the "causal" genomic events involved in mammary carcinogenesis in vivo. One important mechanism that can give rise to the unstable genome in breast cancer is the dysfunction of telomeres, the physical termini of chromosomes that protect natural chromosomal ends from being recognized as damaged DNA and inhibit inappropriate DNA repair. On the other hand, recent systematic genomic analyses in human breast carcinomas have revealed that tumor suppressor p53 is the most commonly alerted gene, predominantly through missense mutations that result in accumulation of mutant p53 protein to acquire oncogenic gain-of-function. To faithfully resemble these two important features observed in human breast carcinomas, chromosomal instability and expression of gain- of-function mutant p53, we have been engineering a novel mouse breast cancer model bearing dysfunctional telomere-induced chromosomal instability and expression of "hot spot" gain-of-function mutant p53 in breast epithelium. Our preliminary results suggest that telomere uncapping causes dysfunctional telomeres that activate DNA Damage Response (DDR)-mediated apoptotic pathway to suppress chromosomal instability- driven tumorigenesis in the absence of p53, while "hot spot" mutant p53 inhibits telomere uncapping-induced cell death and promotes cell transformation. Furthermore, we observe that mutant p53 cooperates with dysfunctional telomeres in breast epithelium to promote tumor progression to invasive breast carcinomas in vivo. In this application, we will test our hypothesis that gain-of-function mutant p53 inhibits telomere uncapping-induced DDR-mediated apoptosis to enhance chromosomal instability-driven mammary carcinogenesis in vivo. The two specific aims are designed to test the hypothesis. In Aim 1, we will generate mouse models to test the possibility that gain-of-function mutant p53 cooperates with telomere uncapping- initiated chromosomal instability to promote mammary carcinogenesis in vivo. In Aim 2, we will investigate the molecular mechanism underlying gain-of-function mutant p53 promotes chromosomal instability-driven breast tumor development. We anticipate that our engineered chromosomal instability mouse models will faithfully recapitulate the complex cytogenetic aberrations of human breast cancer and help us identify novel molecular targets to improve strategies for the prevention and treatment of breast cancer.