RRC ID 52889
Author Shibata W, Kinoshita H, Hikiba Y, Sato T, Ishii Y, Sue S, Sugimori M, Suzuki N, Sakitani K, Ijichi H, Mori R, Endo I, Maeda S.
Title Overexpression of HER2 in the pancreas promotes development of intraductal papillary mucinous neoplasms in mice.
Journal Sci Rep
Abstract Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival rate of less than 5% and is the sixth leading cause of cancer death. Although KRAS mutations are one of the major driver mutations in PDA, KRAS mutation alone is not sufficient to induce invasive pancreatic cancer in mice model. HER2, also known as ERBB2, is a receptor tyrosine kinase, and overexpression of HER2 is associated with poor clinical outcomes in pancreatic cancer. However, no report has shown whether HER2 and its downstream signaling contributes to the pancreatic cancer development. By immunohistochemical analysis in human cases, HER2 protein expression was detected in 40% of PDAs and 29% of intraductal papillary mucinous carcinomas, another type of pancreatic cancer. In a mouse model, we showed overexpression of activated HER2 (HER2 NT ) in the pancreas, in which cystic neoplastic lesions resembling intraductal papillary mucinous neoplasm-like lesions in humans had developed. We also found that HER2 NT cooperated with oncogenic Kras to accelerate the development of pancreatic intraepithelial neoplasms. In addition, using pancreatic organoids in 3D cultures, we found that organoids cultured from HER2 NT /Kras double transgenic mice showed proliferative potential and tumorigenic ability cooperatively. HER2-signaling inhibition was suggested to be an new therapeutic target in some types of PDAs.
Volume 8(1)
Pages 6150
Published 2018-4-18
DOI 10.1038/s41598-018-24375-2
PII 10.1038/s41598-018-24375-2
PMID 29670173
PMC PMC5906617
MeSH Adenocarcinoma, Mucinous / genetics* Adenocarcinoma, Mucinous / metabolism Adenocarcinoma, Mucinous / pathology Adenocarcinoma, Papillary / genetics* Adenocarcinoma, Papillary / metabolism Adenocarcinoma, Papillary / pathology Animals Biomarkers, Tumor Carcinoma, Pancreatic Ductal / genetics* Carcinoma, Pancreatic Ductal / metabolism Carcinoma, Pancreatic Ductal / pathology Cell Transformation, Neoplastic / genetics* Disease Models, Animal Gene Expression* Immunohistochemistry Mice Mutation Pancreas / metabolism* Pancreas / pathology Proto-Oncogene Proteins p21(ras) / genetics Receptor, ErbB-2 / antagonists & inhibitors Receptor, ErbB-2 / genetics* Receptor, ErbB-2 / metabolism
IF 3.998
Times Cited 4
DNA material pCALNL5 (RDB01862).