Malignant transformation of the esophageal mucosa is enhanced in p27 knockout mice

Objective: In a previous study, we showed that experimentally induced gastr oduodenal-esophageal reflux in mice treated with a carcinogen can result in Barrett esophagus and Barrett-associated adenocarcinoma. Since we have sho wn that most Barrett-associated adenocarcinomas in human beings have lost t he tumor suppressor gene p27, we sought to determine whether cancer would b e more likely to develop in p27 knockout mice than in p27 heterozygous or p 27 wild type mice. Methods: Three groups of mice were treated by esophagojejunostomy resulting in gastroduodenal-esophageal reflux and by a carcinogen (N-methyl-N-benzyl nitrosamine): group 1 (50 wild type), group II (45 p27 heterozygous), and g roup III (50 p27 knockout). The mice were killed 18 to 20 weeks after opera tion and studied macroscopically and histopathologically. Results: Barrett esophagus developed in 7 (14%) mice in group 1, 4 (8.9%) m ice in group II, and 13 (26%) mice in group III. Cancers developed in 30 (6 0%) mice in group I, 31 (68%) mice in group II, and 43 (86%) mice in group III. Ten percent of the cancers in group I were adenocarcinomas, as were 16 .1% in group II, and 23.3% in group III. The difference between rates of Ba rrett esophagus in groups I and II compared with group III was statisticall y significant (P =.035), as was true of the cancer rates (P =.006). The per centage of cancers that were adenocarcinomas was highest in group III, but not significantly different from groups I and II. Conclusions: This experimental mouse model of Barrett esophagus and Barrett -associated adenocarcinoma is similar to what occurs in human beings and ma y be useful in developing methods to inhibit malignant transformation of Ba rrett esophagus.