The Role of AGR2 in a Murine Model of Pancreatic Adenocarcinoma

描述（由申请人提供）：胰腺腺癌是美国癌症相关死亡的第四大原因。目前还没有有效的治疗方法。本申请是基于AGR2基因对胰腺癌的形成或传播至关重要的假设，并提出在具有良好特征的胰腺腺癌动物模型中检验AGR2基因的重要性。该实验室之前的工作证实，AGR2基因在所有胰腺腺癌中都有活性表达。对腺癌细胞系的进一步研究证实，AGR2促进了细胞生长和转移的特征。由于最初的实验是在体外培养的细胞中进行的，因此必须在整个动物中验证AGR2的重要性。胰腺癌的最新进展已经产生了几种基因工程小鼠模型，这些模型密切反映了人类胰腺癌的发展和进展。这些模型为评估影响胰腺癌生物学的因素提供了宝贵的资源。K-ras基因在90%以上的胰腺癌中发生突变。当突变的K-ras基因在小鼠胰腺中表达时，就会产生与人类相似的早期癌前病变。这些病变中有一小部分会发展为癌症。当将涉及p53基因的第二个突变添加到同一小鼠模型中时，几乎所有的小鼠都会患上腺癌，其中许多还会转移。本申请旨在检测在上述两种小鼠模型中基因删除AGR2基因后是否会影响胰腺腺癌的病程。如果癌前病变或癌症的形成或传播被AGR2的缺失成功破坏，这将为该基因的重要作用提供强有力的证据，并为治疗干预提供新的靶点。该申请代表了我们提供关于AGR2基因与胰腺癌生物学相关性的额外数据的重新提交。此外，我们还提供数据支持我们的能力，以产生基因定义的小鼠模型，如前所述。

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is the fourth leading cause of cancer related death in the United States. Effective therapies currently do not exist. This application is based on the hypothesis that the AGR2 gene is essential for the formation or propagation of pancreatic cancer, and proposes to test the AGR2 gene's importance in a well-characterized animal model for pancreatic adenocarcinoma. The laboratory's previous work established that the AGR2 gene is actively expressed in all pancreatic adenocarcinomas. Additional studies using adenocarcinoma cell lines established that AGR2 promotes cell growth and features that are characteristic of metastasis. Because the initial experiments were performed in cell cultures grown in vitro, validation of AGR2's significance must be established in a whole animal. Recent advances in pancreatic cancer have produced several genetically engineered mouse models that closely reflect the development and progression of human pancreatic cancer. These models serve as a valuable resource to evaluate factors that influence the biology of pancreatic cancer. The K-ras gene is mutated in over 90% of pancreatic cancers. When the mutated K-ras gene is expressed in the mouse pancreas, early premalignant lesions similar to those observed in humans result. A small proportion of these lesions will progress to frank cancer. When a second mutation involving the p53 gene is added to the same mouse model, almost all of the mice will develop adenocarcinomas, of which many will also metastasize. This application proposes to examine whether the course of pancreatic adenocarcinoma is affected after genetically deleting the AGR2 gene in the two mouse models described. If the formation or propagation of premalignant lesions or cancer is successfully compromised by AGR2's absence, it would provide strong evidence of the gene's important role and provide a novel target for therapeutic intervention. This application represents a resubmission in which we provide additional data concerning the biologic relevance of the AGR2 gene to pancreatic cancer. In addition, we also provide data supporting our ability to produce the genetically defined mouse models as previously described. PUBLIC HEALTH RELEVANCE: Pancreatic adenocarcinoma is the fourth leading cause of cancer related death in the United States. The laboratory previously determined that the AGR2 gene is highly expressed in all pancreatic adenocarcinomas. This application proposes to evaluate in a well-established animal model whether the AGR2 gene is necessary for the formation or propagation of pancreatic cancer.