The incidence of esophageal adenocarcinoma (EAC) is rising rapidly throughout the Western world, and is associated with gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE). BE is intestinal metaplasia of squamous esophageal epithelium, important clinically due to the fact that it increases an individual's chance of progression to EAC 30 to 125-fold higher than people without BE. Despite its clinical importance, the molecular pathogenesis of BE is poorly understood. One limitation in the study of BE pathogenesis has been the lack of suitable experimental models. There is a critical need to develop good preclinical models of BE. ErbB2 was reported to be amplified and overexpressed in BE, EAC, and esophageal squamous cell carcinoma (ESCC). However, the role of erbB2 in the development and progression of esophageal cancer is still unknown. In this study, we utilized BK5.erbB2 mice, in which erbB2 is overexpressed in epithelial cells under the control of the bovine keratin 5 promoter to determine whether the interaction between erbB2 and bile acids is important in the etiology of esophageal cancers. BK5.erbB2 mice (2 months of age, n=8) and age matched wild type mice (n=10) were treated with porcine bile extract (10mg/mouse in 200μL water), taurochenodeoxycholate (TCDC) (0.1μmol/mouse in 200μL water), or water control, 3 times weekly for 14 weeks by gavage. In the BK5.erbB2 mice, exophytic tumors in the forestomach, which has the same histological structure of esophagus, were observed in 20%, 33%, and 0% of mice treated with bile extract, TCDC, and water control, respectively. No tumors were observed in wild type mice. All tumors observed in BK5.erbB2 mice were diagnosed as SCC. Western blotting analysis demonstrated that the bile acid treatment increased the levels of p-EGFR, p-MAPK, and p-Akt in the forestomachs of the BK5.erbB2 mice. Furthermore, CDX2 (a marker of BE) was significantly expressed in BK5.erbB2 mice treated with bile extract or TCDC. No development of intestinal metaplasia in forestomach was found. We further investigated using a surgically manipulated reflux model. Eleven 7 week-old BK5.erbB2 and 5 wild type mice were given an esophagogastroduodenostomy. Mice were sacrificed at post-operative week 8, and examined histologically. Hyperkeratosis and intestinal metaplasia were observed at the anastomosis sites in both BK5.erbB2 and wild type mice. These histological changes were more prominent in BK5.erbB2 mice. Interestingly, dysplastic lesions were observed only in BK5.erbB2 mice. These results indicate that more persistent exposure of bile via surgery induce the development of not only SCC, but also precancerous lesions of adenocarcinoma in the esophagus/forestomach of BK5.erbB2 mice. The interaction between erbB2 and bile acids is important in esophageal tumor formation and intestinal metaplasia. A surgical model using BK5.erbB2 mice could possibly be a promising model for the study of the development of EAC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1331. doi:1538-7445.AM2012-1331