Role of ATBF1 inactivation in the development and progression of prostate cancer

ATBF1失活在前列腺癌发生和进展中的作用

• 批准号: 7223401
• 负责人: JIN-TANG DONG
• 金额: $ 26.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-14 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7223401
• 关键词: 12p12; 16q22; 8p21; Adult; Affect; CDKN1A gene; CDKN1B gene; Cancer Biology; Cancer Patient; Cell Proliferation; Cells; Chromosome Deletion; Chromosomes, Human, Pair 16; DNA; Data; Deletion Mutation; Development; Diagnosis; Embryonic Development; Epigenetic Process; Event; Gene Deletion; Gene Mutation; Gene Targeting; Genes; Genetic; Genomics; In Vitro; Individual; Knock-out; Knockout Mice; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; Modeling; Molecular; Mus; Mutation; NKX3-1 gene; Nature; Nucleotides; Oncogene Proteins; PTEN gene; Phenotype; Play; Preneoplastic Change; Prostate; Prostatic; Protein Overexpression; Publishing; Role; Sampling; Somatic Mutation; Structure of base of prostate; Suppressor Genes; Testing; Transgenic Organisms; Tumor Suppressor Genes; Tumor Suppressor Proteins; age related; alpha-Fetoproteins; cancer cell; cancer diagnosis; carcinogenesis; cell growth; clinically significant; cyclin-dependent kinase inhibitor 1B; functional loss; knockout gene; loss of function; men; mouse model; oncoprotein p21; outcome forecast; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; promoter; transcription factor; tumor

DESCRIPTION (provided by applicant): The molecular basis of prostate cancer is still poorly understood, and thus identifying and characterizing genes underlying prostate cancer remains an important task. In our preliminary studies, we have identified the ATBF1 transcription factor as a strong candidate for a tumor suppressor gene at the q22 band of chromosome 16 (16q22), one of the most frequently deleted chromosomal regions in prostate cancer (Nature Genetics 2005, in press). We first narrowed the region of deletion at 16q22 to 861-Kb, which contains the ATBF1 gene. We then found that the expression of ATBF1 is at higher levels in normal prostates but is significantly reduced in prostate cancer cells. Furthermore, expression of ATBF1 suppressed cell proliferation or survival. Most notable is that ATBF1 undergoes frequent somatic mutations in human prostate cancer, as 35 mutations of ATBF1 have been detected in 24 of 66 (36%) cancer samples and many of the mutations clearly interrupt ATBF1 function. A 21/24-nucleotide deletion also occurred in the germline of some prostate cancer patients but has not been detected in normal controls. We therefore hypothesize that ATBF1 is a tumor suppressor gene whose loss of function by genomic deletion, mutation, or loss of expression contributes to the development and progression of prostate cancer. This hypothesis is also supported by some published and unpublished studies from other groups. In this proposal, we will further test this hypothesis in four specific aims. First, we will determine if the 21/24-nucleotide deletion of ATBF1 plays a role in human prostate cancer by performing genetic and functional analyses. Second, we will generate a mouse model in which ATBF1 will be specifically knocked out in the prostates of adult mice, and investigate phenotypic alterations resulting from the loss of ATBF1 function. Third, we will examine the role of ATBF1 deletion in prostate cancer in the context of PTEN inactivation, which is also frequently deleted in human prostate cancer. Finally, in aim 4 we will examine if loss of ATBF1 cooperates with loss of NKX3.1 in inducing prostate cancer. The latter is from another frequently deleted chromosomal region in prostate cancer. Completion of these studies will clarify the role of ATBF1 in prostatic carcinogenesis, and will likely present a target that is potentially useful for the diagnosis and prognosis of prostate cancer, as well as for the study of prostate cancer biology.

描述（由申请人提供）：前列腺癌的分子基础仍然知之甚少，因此鉴定和表征前列腺癌的基因仍然是一项重要的任务。在我们的初步研究中，我们已经确定 ATBF1 转录因子是 16 号染色体 q22 带 (16q22) 肿瘤抑制基因的有力候选基因，该带是前列腺癌中最常缺失的染色体区域之一（Nature Genetics 2005，出版中）。我们首先将 16q22 的缺失区域缩小到 861-Kb，其中包含 ATBF1 基因。然后我们发现 ATBF1 的表达在正常前列腺中处于较高水平，但在前列腺癌细胞中显着降低。此外，ATBF1 的表达抑制细胞增殖或存活。最值得注意的是，ATBF1 在人类前列腺癌中经历频繁的体细胞突变，在 66 个癌症样本中的 24 个 (36%) 中检测到了 35 个 ATBF1 突变，并且许多突变明显中断了 ATBF1 功能。一些前列腺癌患者的种系中也发生了 21/24 核苷酸缺失，但在正常对照中未检测到。因此，我们假设 ATBF1 是一种抑癌基因，其因基因组缺失、突变或表达缺失而丧失功能，导致前列腺癌的发生和进展。这一假设也得到了其他小组的一些已发表和未发表的研究的支持。在本提案中，我们将在四个具体目标上进一步检验这一假设。首先，我们将通过进行遗传和功能分析来确定 ATBF1 的 21/24 核苷酸缺失是否在人类前列腺癌中发挥作用。其次，我们将建立一个小鼠模型，其中 ATBF1 将在成年小鼠的前列腺中被特异性敲除，并研究由于 ATBF1 功能丧失而导致的表型改变。第三，我们将在 PTEN 失活的背景下研究 ATBF1 缺失在前列腺癌中的作用，PTEN 失活也经常在人类前列腺癌中缺失。最后，在目标 4 中，我们将检查 ATBF1 的缺失是否与 NKX3.1 的缺失共同诱导前列腺癌。后者来自前列腺癌中另一个经常缺失的染色体区域。这些研究的完成将阐明 ATBF1 在前列腺癌发生中的作用，并可能为前列腺癌的诊断和预后以及前列腺癌生物学研究提供潜在有用的靶点。