SAFB1 /2 Factors as Noval Breast Tumor Suppressor Genes

SAFB1 /2 作为新型乳腺肿瘤抑制基因

• 批准号: 6989323
• 负责人: Steffi Oesterreich
• 金额: $ 17.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989323
• 关键词: RNA interference; breast neoplasms; disease /disorder model; female; gene expression; gene mutation; genetic mapping; genetic regulation; genetically modified animals; human genetic material tag; immunocytochemistry; laboratory mouse; molecular oncology; neoplasm /cancer genetics; neoplastic growth; nuclear matrix; oncoproteins; polymerase chain reaction; transcription factor; tumor suppressor genes; tumor suppressor proteins; women' s health

DESCRIPTION (provided by applicant): We have recently identified and characterized two scaffold attachment factors termed SAFB1 and SAFB2, which show 75 percent homology and map together (in head-to-head orientation) on chromosome 19p13. We have discovered that the SAFBs function as growth inhibitors in breast cancer cells, and that their locus on chromosome 19p13 displays one of the highest losses of heterozygosity (78 percent) reported in clinical breast cancer. Protein expression of SAFB1/2 is lost in approximately 20 percent of breast cancers, and low expression is associated with a shorter overall survival. We have found SAFB1 mutations in breast tumors that are not present in adjacent normal tissue. Therefore, we hypothesize that SAFB1 and SAFB2 are tumor suppressors whose frequent inactivation in breast tumors results in tumorigenic and metastatic phenotypes, which we will assess using in vivo and in vitro models. While both proteins function as growth inhibitors and ER co-repressors, they also have distinct properties - both are found in the cell nucleus, but only SAFB1 is recruited to nuclear bodies under stress conditions, and only SAFB2 also appears in the cytoplasm and binds vinexin-beta. We will therefore assess which SAFB functions are essential for tumor suppression, and which functions are additive, synergistic, compensatory, or antagonistic between SAFB1 and SAFB2. Specifically, we will ask: 1) How are SAFB1/2 inactivated in human breast tumors? We will investigate loss during breast cancer evolution, and determine whether inactivation occurs through mutations and/or other epigenetic events such as hypermethylation of the intergenic bidirectional SAFB1/2 promoter. 2) What are the biological effects of neutralizing SAFB1 in vitro and in vivo? We will compare and contrast the effects of lowering (by RNAi) SAFB1 and SAFB2, of SAFB mutants identified in clinical breast cancer specimens, and of gene knockouts in mouse models (SAFB1-/- and SAFB2-/-). 3) How do SAFB1 and SAFB2 levels correlate with clinical breast cancer outcome? We will measure SAFB1 and SAFB2 levels in an arrayed breast tumor bank, and correlate the levels with survival and other known prognostic factors. Successful completion of this study, which incorporates molecular, cellular, and in vivo genetic approaches, will provide important insight into regulatory mechanisms which are critically disturbed in human breast cancer.

描述（由申请人提供）：我们最近鉴定并表征了两种称为SAFB 1和SAFB 2的支架附着因子，它们显示75%的同源性并一起定位（以头对头方向）在染色体19 p13上。我们发现SAFB在乳腺癌细胞中起生长抑制剂的作用，并且它们在染色体19 p13上的基因座显示出临床乳腺癌中报告的最高杂合性丢失（78%）之一。SAFB 1/2的蛋白表达在大约20%的乳腺癌中丢失，低表达与较短的总生存期相关。我们在乳腺肿瘤中发现了SAFB 1突变，而在邻近的正常组织中不存在。因此，我们假设SAFB 1和SAFB 2是肿瘤抑制因子，其在乳腺肿瘤中的频繁失活导致致瘤性和转移性表型，我们将使用体内和体外模型进行评估。虽然这两种蛋白质都是生长抑制剂和ER共抑制剂，但它们也具有不同的特性-两者都存在于细胞核中，但只有SAFB 1在应激条件下被招募到核体中，只有SAFB 2也出现在细胞质中并结合vinexin-β。因此，我们将评估哪些SAFB功能是肿瘤抑制所必需的，哪些功能是SAFB 1和SAFB 2之间的相加、协同、补偿或拮抗。具体来说，我们将问：1）SAFB 1/2在人类乳腺肿瘤中是如何失活的？我们将研究乳腺癌演变过程中的丢失，并确定是否通过突变和/或其他表观遗传事件（如基因间双向SAFB 1/2启动子的超甲基化）发生失活。2)中和SAFB 1在体外和体内的生物学效应是什么？我们将比较和对比降低（通过RNAi）SAFB 1和SAFB 2、临床乳腺癌标本中鉴定的SAFB突变体以及小鼠模型中的基因敲除（SAFB 1-/-和SAFB 2-/-）的效果。3)SAFB 1和SAFB 2水平与乳腺癌临床结局有何关系？我们将测量阵列乳腺肿瘤库中的SAFB 1和SAFB 2水平，并将该水平与生存率和其他已知的预后因素相关联。这项研究的成功完成，它结合了分子，细胞和体内遗传学的方法，将提供重要的洞察调控机制，这是严重干扰人类乳腺癌。