The role of DEK in breast cancer development and therapy

描述（由申请人提供）：乳腺癌是美国女性癌症相关死亡的第二大原因。尽管人们努力提高认识并开发新的治疗方法，但关于乳腺癌的分子病因学还有很多需要了解。因此，鉴定新的乳腺癌相关蛋白的特征是很重要的，这些蛋白可能用于诊断、预后和作为最佳治疗方案的标记。人类DEK基因首次在AML患者中被鉴定为与CAN/NUP214核孔蛋白基因融合。它是增殖细胞中普遍表达的染色质结合蛋白，在转录调节、DNA拓扑、复制和修复中具有潜在的作用。DEK作为一种原癌基因，可能通过调控p53蛋白家族，抑制原代角化细胞和宫颈癌细胞的衰老、分化和凋亡。然而，其在体内的致癌活性仍然知之甚少。人类DEK基因在造血癌和实体瘤中的基因扩增和mRNA表达上调已被描述。使用Oncomine和我的初步数据进行的meta分析表明，它也可能对乳腺癌的发病机制很重要：与正常乳腺组织相比，在原发性和培养的乳腺癌中观察到DEK mRNA和蛋白过表达，并且过表达与几个临床病理变量密切相关。在包括乳腺癌在内的大多数癌症中，DEK蛋白的表达和潜在的致癌活性尚未得到研究。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，我假设DEK通过干扰细胞周期检查点和DNA损伤反应途径参与乳腺癌的发展。为了验证这一假设，我们提出了三个具体的目的：(1)确定DEK在小鼠和人类原发性乳腺癌标本和培养细胞系中的表达是否升高；(2)确定DEK上调是否刺激乳腺癌细胞培养和异种移植模型的肿瘤表型；(3)阐明DEK在乳腺癌体内发展中的作用。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，以支持未来的临床前研究。我们实验室最近的数据支持将DEK作为一种潜在的临床方法，发现细胞增殖率与DEK耗竭后的细胞死亡程度直接相关：分化的细胞不敏感，而快速增殖的肿瘤细胞则会发生剧烈的细胞死亡。我们推测DEK在乳腺癌中的靶向治疗可能具有治疗价值。

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.