Malignant transformation of the esophageal mucosa is enhanced in p27 knockout mice.
OBJECTIVE
In a previous study, we showed that experimentally induced gastroduodenal-esophageal reflux in mice treated with a carcinogen can result in Barrett esophagus and Barrett-associated adenocarcinoma. Since we have shown that most Barrett-associated adenocarcinomas in human beings have lost the tumor suppressor gene p27, we sought to determine whether cancer would be more likely to develop in p27 knockout mice than in p27 heterozygous or p27 wild type mice.


METHODS
Three groups of mice were treated by esophagojejunostomy resulting in gastroduodenal-esophageal reflux and by a carcinogen (N -methyl-N -benzylnitrosamine): group I (50 wild type), group II (45 p27 heterozygous), and group III (50 p27 knockout). The mice were killed 18 to 20 weeks after operation and studied macroscopically and histopathologically.


RESULTS
Barrett esophagus developed in 7 (14%) mice in group I, 4 (8.9%) mice in group II, and 13 (26%) mice in group III. Cancers developed in 30 (60%) 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 Barrett esophagus in groups I and II compared with group III was statistically significant (P =.035), as was true of the cancer rates (P =.006). The percentage 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 may be useful in developing methods to inhibit malignant transformation of Barrett esophagus.
Ellis
F H
FH
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Xu
X
X
Kulke
M H
MH
LoCicero
J
J
Loda
M
M
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004947:Esophagus / Q000473:pathology*; D016147:Genes, Tumor Suppressor; D051379:Mice; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27