Abstract 4176: Bile acid-promoted esophageal and forestomach carcinomas in BK5.erbB2 mice
Authors: Takuya Kitamura, Kevin Connolly, Aline Lueckgen, John DiGiovanni, Kaoru Kiguchi
Journal: Cancer Research (2010)

Abstract Esophageal cancer is considered to be one of the most lethal cancers, with a 5-year survival rate of approximately 23% to 50% for patients, even after complete resection with lymph node dissection. There are two common forms of esophageal cancer: squamous cell carcinomas (ESCCs) and adenocarcinomas (EACs). It has been shown that the initial step in the development of EACs is the transformation of normal stratified squamous epithelium in the lower esophagus to metaplastic specialized columnar epithelium (SCE), a pathological condition caused by chronic gastroesophageal reflux of gastric acid and bile known as Barrett's esophagus (BE), and it is possible that this condition also leads to the development of ESCCs as well. Although it has been reported that erbB2 is strongly expressed in SCE, EACs, and ESCCs, the role of erbB2 in the development and progression of esophageal cancer is still unknown. Furthermore, the contribution of bile acids in the etiology of esophageal cancer has not been explored. In this study, to determine whether interaction between erbB2 and bile acids is important in the etiology of esophageal cancers, we utilized BK5.erbB2 mice, in which erbB2 is overexpressed in epithelial cells under the control of the bovine keratin 5 promoter. Eight two-month-old homozygous BK5.erbB2 mice and 8 wild type mice were initiated with N-nitrosomethylbenzylamine (NMBA, 50μg/mouse in 200μL water, twice weekly for 3 consecutive weeks). Mice were then treated with porcine bile extract (10mg/mouse in 200μL water, 3 times weekly for 4 weeks) by gavage. Mice were sacrificed 24 hours after the last treatment and histopathological analyses in the esophagus, forestomach, squamocolumnar junction within the glandular stomach, and other tissues were performed. In wild type mice, only 20% of mice treated with NMBA/bile extract developed small papillomas in the forestomach and squamocolumnar junction at the stomach. In BK5.erbB2 mice, 50% of mice treated with bile extract alone developed significant hyperplasia, 63% of mice treated with NMBA alone developed papillomas, and 100% of mice treated with NMBA/bile extract developed large SCCs in these areas. BK5.erbB2 mice treated with bile extract also showed significantly elevated levels of cell proliferation as determined by 5-bromo-2′-deoxyuridine incorporation in esophagus and forestomach compared to wild type mice. These results indicate that bile acids may play an important role in the development of stomach/esophageal tumors where erbB2 is overexpressed and/or activated. In this regard, bile acids may promote the development of these tumors. Furthermore, these studies demonstrate the utility of the BK5.erbB2 mouse as a novel model for human stomach and esophageal cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4176.