Chromatin associated functions of the APC tumor suppressor

描述(申请人提供)：在一生中，大约5%的美国人患上结直肠癌，超过三分之一的人死于这种疾病。当低位肠道衬里的细胞发生基因突变，导致大肠息肉的生长和增殖时，结直肠癌就开始发展。如果不切除，这种癌前生长最终会发展成恶性肿瘤。一种常见的突变类型，在大约80%的结直肠癌中发现，导致APC蛋白缺陷，APC蛋白以结肠癌易感性家族性腺瘤性息肉病结肠的遗传综合征命名。这种蛋白质的缺陷会引发息肉的形成。关键是要确定APC缺乏如何使息肉形成和 为了开发肿瘤预防和治疗的新治疗策略，我们将继续研究癌症的新进展。最近的研究表明，APC是一种具有DNA结合能力的细胞质和核蛋白，它与MYC原癌基因上游的一个增强子位点结合，这是一个已知的Wnt靶点，直接下调其转录(Sierra等人，2006年)。我们假设APC类似地调节与肿瘤发生相关的其他靶点，与其他20%的结直肠癌相比，APC缺陷的80%的结直肠癌可能表现出这些基因的异常激活或抑制。这可能会导致这两组癌症对化疗的反应不同，并可能有助于解释为什么某些疗法对一些患者有利，而对另一些患者没有好处。我们的初步基因组和信息学数据显示，在Wnt信号被激活但APC完整的结直肠癌细胞中，APC的丢失会导致近200个基因的异常激活或抑制。这些拟议的研究将确定这些基因中的哪些真正受APC与DNA的相互作用控制，APC控制它们的机制，以及它们中的哪些对肿瘤的发展是重要的。不同阶段和级别的患者肿瘤样本将被测试这些基因的激活或抑制。如果某些基因的变化与临床表型有关，那么检测患者的这些变化可能会导致更准确的预后和改善治疗决策。APC激活或抑制的基因可以被开发的针对APC缺陷的结直肠癌的新药靶向。

DESCRIPTION (provided by applicant): Over a lifetime, roughly 5% of Americans develop colorectal cancer, and more than a third do not survive the disease. Colorectal cancer begins to develop when cells in the lining of the lower intestine suffer genetic mutations that cause growth and proliferation into a colorectal polyp. If not removed, this pre-cancerous growth eventually develops into a malignant tumor. One common type of mutation, found in approximately 80% of colorectal cancers, causes defects the APC protein, named after the inherited syndrome of colon cancer predisposition familial adenomatous polyposis coli. Defects in this protein trigger the formation of a polyp. It is critical to identify how APC deficiency enables a polyp to form and progress into cancer in order to develop new therapeutic strategies for tumor prevention and treatment. Recent studies have shown that APC, a cytoplasmic and nuclear protein with DNA-binding capability, binds an enhancer site upstream of the MYC proto-oncogene, a known Wnt target, to downregulate its transcription directly (Sierra et al., 2006). We hypothesize that APC similarly regulates other targets relevant to tumorigenesis, and that the 80% of colorectal cancers that are deficient in APC may show abnormal activation or suppression of these genes, in comparison to the other 20% of colorectal cancers. This could potentially cause these two groups of cancers to respond differently to chemotherapy, and may help explain why certain therapies benefit some patients but not others. Our preliminary genomic and informatics data show that in colorectal cancer cells with activated Wnt signaling but intact APC, the loss of APC causes abnormal activation or suppression of nearly 200 genes. These proposed studies will identify which of those genes are truly controlled by the interaction of APC with DNA, the mechanism by which APC controls them, and which of them are important for tumor development. Patient tumor samples of different stages and grades will be tested for activation or suppression of these genes. If changes in certain genes are associated with clinical phenotypes, then testing for these changes in patients may lead to more accurate prognosis and improve treatment decisions. Genes activated or suppressed by APC can be targeted by new drugs developed against APC-deficient colorectal cancers.