Identification and characterization of tumor suppressor genes in prostate cancer

描述（由申请人提供）：对前列腺癌的生物学知之甚少，鉴定和表征其改变导致前列腺癌的基因仍然是一项重要任务。我们的总体假设是，频繁缺失的染色体区域含有肿瘤抑制基因，其通过缺失、基因突变和/或表达缺失而失活是致癌的常见原因。这一假设已经通过对来自10 q23的PTEN、来自12 p12的p27和来自8 p21的NKX 3 -1的敲除小鼠研究得到验证。在先前资助的支持下，我们对三个染色体区域13 q14、6 q15和16 q22进行了缺失作图和基因鉴定，每个区域在人类前列腺癌中经常缺失。我们的遗传和功能研究已经确定FOXO 1A转录因子、RNU 50 snoRNA和ATBF 1转录因子分别为13 q14、6 q15和16 q22区域的肿瘤抑制基因的合理候选者。16 q22处的ATBF 1基因可能是最有趣的，因为它不仅被删除和下调，而且在前列腺癌中还具有频繁的体细胞突变（Sun et al.，Nature Genetics 37：407-412，2005）。此外，ATBF 1的异位表达抑制和敲低ATBF 1增强细胞增殖或存活。已发表的研究表明，ATBF 1与其他分子相互作用以调节基因表达。因此，我们假设ATBF 1是一种真正的肿瘤抑制基因，其失活通过改变与其他调节细胞增殖和基因表达的分子的相互作用而导致前列腺癌。我们将在三个具体目标中检验这一假设。1)使用体外和体内系统对ATBF 1突变进行功能评价。我们将首先确定在人类前列腺癌中检测到的突变是否会在体外损害ATBF 1的结构和功能。然后，我们将研究ATBF 1在小鼠中的失活是否会导致前列腺癌。2)评估ATBF 1改变对前列腺癌不同临床和病理学方面的影响。3)测试ATBF 1是否与其他分子相互作用以调节基因表达，并确定哪些分子参与相互作用以及哪些基因受到相互作用的调节。这些研究应该阐明ATBF 1在前列腺癌中的作用，建立与人类疾病相关的小鼠前列腺癌模型，并揭示前列腺癌发生的新途径。它们也可以将ATBF 1作为有用的生物标志物。

DESCRIPTION (provided by applicant): The biology of prostate cancer is poorly understood, and it is still an important task to identify and characterize the genes whose alterations contribute to prostate cancer. Our overall hypothesis is that frequently deleted chromosomal regions harbor tumor suppressor genes whose inactivation through deletion, gene mutation, and/or loss of expression is a common cause of carcinogenesis. This hypothesis has been validated by knockout mouse studies for PTEN from 10q23, p27 from 12p12, and NKX3-1 from 8p21. With the support of the previous grant, we performed deletion mapping and gene identification for three chromosomal regions, 13q14, 6q15, and 16q22, each of which is frequently deleted in human prostate cancer. Our genetic and functional studies have established FOXO1A transcription factor, RNU50 snoRNA, and ATBF1 transcription factor as reasonable candidates for tumor suppressor genes at the 13q14, 6q15, and 16q22 regions respectively. The ATBF1 gene at 16q22 may be the most interesting, because it is not only deleted and downregulated, it also has frequent somatic mutations in prostate cancer (Sun et al., Nature Genetics 37:407-412, 2005). Furthermore, ectopic expression of ATBF1 suppressed and knockdown of ATBF1 enhanced cell proliferation or survival. Published studies suggest that ATBF1 interacts with other molecules to regulate gene expression. We therefore hypothesize that ATBF1 is a bona fide tumor suppressor gene whose inactivation leads to prostate cancer through altered interactions with other molecules regulating cell proliferation and gene expression. We will test this hypothesis in three specific aims. 1) Functionally evaluate ATBF1 mutations using in vitro and in vivo systems. We will first determine if mutations detected in human prostate cancers impair ATBF1 structure and function in vitro. We will then examine if inactivation of ATBF1 in mice causes prostate cancer. 2) Assess the effect of ATBF1 alterations on different clinical and pathological aspects of prostate cancer. 3) Test if ATBF1 interacts with other molecules to regulate gene expression, and identify what molecules are involved in the interaction and what genes are regulated by the interaction. These studies should clarify the role of ATBF1 in prostate cancer, establish a mouse prostate cancer model that is relevant to human disease, and uncover a new pathway underlying prostatic carcinogenesis. They may also present ATBF1 as a useful biomarker.