The Role of AGR2 in a Murine Model of Pancreatic Adenocarcinoma

描述（由申请人提供）：胰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。本申请基于AGR 2基因对于胰腺癌的形成或增殖是必需的这一假设，并提出在充分表征的胰腺癌动物模型中测试AGR 2基因的重要性。该实验室以前的工作确定AGR 2基因在所有胰腺癌中表达活跃。使用腺癌细胞系的其他研究确定AGR 2促进细胞生长和转移特征。由于最初的实验是在体外生长的细胞培养物中进行的，因此必须在整个动物中建立AGR 2的重要性的验证。 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。这些模型是评估影响胰腺癌生物学因素的宝贵资源。K-ras基因在超过90%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，产生与在人类中观察到的类似的早期癌前病变。这些病变中的一小部分会发展为坦率的癌症。当涉及p53基因的第二个突变被添加到相同的小鼠模型中时，几乎所有的小鼠都会发展腺癌，其中许多也会转移。本申请提出在所述的两种小鼠模型中检测在遗传上缺失AGR 2基因后胰腺癌的进程是否受到影响。如果癌前病变或癌症的形成或传播被AGR 2的缺失成功地破坏，它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。 本申请是一次重新提交，其中我们提供了关于AGR 2基因与胰腺癌生物学相关性的额外数据。此外，我们还提供了支持我们生产如前所述的遗传定义的小鼠模型的能力的数据。 公共卫生相关性：胰腺癌是美国癌症相关死亡的第四大原因。实验室先前确定AGR 2基因在所有胰腺癌中高度表达。本申请提出在完善的动物模型中评估AGR 2基因是否是胰腺癌形成或增殖所必需的。

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.