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

描述（由申请人提供）：前列腺癌的分子基础仍然知之甚少，因此识别和表征前列腺癌的基因仍然是一项重要任务。在我们的初步研究中，我们已经确定了ATBF1转录因子是位于16号染色体q22带（16q22）的肿瘤抑制基因的强候选基因，这是前列腺癌中最常缺失的染色体区域之一（Nature Genetics 2005, In press）。我们首先将16q22的缺失区域缩小到861-Kb，该区域包含ATBF1基因。我们随后发现，ATBF1在正常前列腺中的表达水平较高，但在前列腺癌细胞中的表达水平明显降低。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常发生体细胞突变，在66个癌症样本中的24个（36%）中检测到35个ATBF1突变，其中许多突变明显中断了ATBF1的功能。21/24核苷酸缺失也发生在一些前列腺癌患者的种系中，但在正常对照中未发现。因此，我们假设ATBF1是一种肿瘤抑制基因，其因基因组缺失、突变或表达缺失而导致的功能丧失有助于前列腺癌的发生和进展。这一假设也得到了其他小组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中进一步验证这一假设。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起作用。其次，我们将在成年小鼠的前列腺中产生特异性敲除ATBF1的小鼠模型，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在人类前列腺癌中也经常缺失。最后，在aim 4中，我们将研究ATBF1的缺失是否与NKX3.1的缺失协同诱导前列腺癌。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。

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 This hypothesis is also supported by some published and unpublished studies from other groups.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.