The role of DEK in breast cancer development and therapy

描述(申请人提供)：乳腺癌是美国女性癌症相关死亡的第二大原因。尽管努力提高认识和开发新的治疗方法，但关于乳腺癌的分子病因学仍有许多需要了解。因此，重要的是确定新的乳腺癌相关蛋白，这些蛋白可用于诊断、预后和作为最佳疗程的标志物。人类DEK基因首次在AML患者中被鉴定为与CaN/NUP214核孔蛋白基因的融合。它在增殖细胞中普遍表达，是染色质结合蛋白，在转录调控、DNA拓扑、复制和修复中具有潜在的作用。作为原癌基因，DEK抑制原代角质形成细胞和宫颈癌细胞的衰老、分化和凋亡，可能是通过调节P53蛋白家族来实现的。然而，它在体内的致癌活性仍然知之甚少。人类DEK基因在血液癌和实体瘤中的基因扩增和上调的mRNA表达已被描述。使用Oncomine和我的初步数据进行的Meta分析表明，它在乳腺癌的发病机制中也可能是重要的：与正常乳腺组织相比，在原代和培养的乳腺癌组织中观察到DEK mRNA和蛋白的过度表达，并且过度表达与几个临床病理变量密切相关。DEK蛋白的表达和潜在的致癌活性在大多数癌症中还没有被研究过，包括乳腺癌。我的初步数据表明，DEK可能通过抑制ATM来影响DNA修复。根据我们的数据，我推测DEK通过干扰细胞周期检查点和DNA损伤反应通路参与乳腺癌的发展。为了验证这一假说，人们提出了三个具体目标：(1)确定DEK在小鼠和人类原发乳腺癌标本和培养细胞系中的表达是否升高；(2)确定在乳腺癌细胞培养和异种移植模型中，DEK上调是否刺激肿瘤表型；以及(3)描述DEK在体内乳腺癌发展中的作用。公共卫生相关性：这些实验将确定DEK在乳腺癌的发生和发展中的作用，并将产生一个小鼠模型系统来支持未来的临床前研究。我们实验室的最新数据支持将DEK作为一种潜在的临床方法，发现细胞增殖率与DEK耗尽后细胞死亡的程度直接相关：分化的细胞不容易受到影响，而快速增殖的肿瘤细胞经历了显著的细胞死亡。我们推测，靶向DEK治疗乳腺癌可能具有治疗价值。

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer-related death among women in the United States. Despite efforts to increase awareness and develop novel treatments, there is much to learn about the molecular etiology of breast cancer. Therefore, it is important to characterize novel breast-cancer related proteins that may be used for diagnosis, prognosis, and as markers for the best course of treatment. The human DEK gene was first identified as a fusion with the CAN/NUP214 nucleoporin gene in AML patients. It is ubiquitously expressed, chromatin-binding protein in proliferating cells with potential roles in transcriptional regulation, DNA topology, replication, and repair. As a proto-oncogene, DEK inhibits cellular senescence, differentiation, and apoptosis in primary keratinocytes and in cervical cancer cells, presumably through regulation of the p53 protein family. However, its oncogenic activities in vivo remain poorly understood. Gene amplification and upregulated mRNA expression have been described for the human DEK gene in hematopoietic cancers and solid tumors. Meta-analysis using Oncomine and my preliminary data indicated that it also may be important for breast cancer pathogenesis: DEK mRNA and protein overexpression was observed in primary and cultured breast cancers compared to normal mammary tissue, and overexpression strongly correlated with several clinico-pathological variables. DEK protein expression and potential oncogenic activity have not been studied in most cancers, including breast cancer. My preliminary data suggest that DEK may influence DNA repair via the repression of ATM. Based on our data, I hypothesize that DEK is involved in breast cancer development through interference with cell cycle checkpoints and DNA damage response pathways. Three specific aims are proposed to test this hypothesis: (1) Determine whether DEK expression is elevated in murine and human primary breast cancer specimens and cultured cell lines; (2) Determine if DEK upregulation stimulates tumor phenotypes in cell culture and xenograft models of breast cancer; and (3) Delineate the role of DEK in breast cancer development in vivo. PUBLIC HEALTH RELEVANCE: These experiments will determine the role of DEK in the initiation and progression of breast cancer, and will generate a murine model system to support future preclinical studies. Recent data from our laboratory support the targeting of DEK as a potential clinical approach with the finding that the rate of cellular proliferation directly correlates with the degree of cell death following DEK depletion: differentiated cells are not susceptible, whereas rapidly proliferating tumor cells undergo dramatic cell death. We hypothesize that the targeting of DEK in breast cancer may be of therapeutic value.