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[Cancer Research 63, 4836-4841, August 15, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Pancreatic ß-Cell-specific Ablation of the Multiple Endocrine Neoplasia Type 1 (MEN1) Gene Causes Full Penetrance of Insulinoma Development in Mice1

Philippe Bertolino, Wei-Min Tong, Pedro Luis Herrera, Huguette Casse, Chang Xian Zhang2 and Zhao-Qi Wang

Genetic and Cancer Laboratory, CNRS, UMR5641, Faculty of Medicine University Lyon 1, 69373, Lyon, France [P. B., H. C., C. X. Z.]; IARC, 69008, Lyon, France [P. B., W-M. T., Z-Q. W.], and Department of Morphology, School of Medicine, University of Geneva, CH-1211 Geneva 4, Switzerland [P. L. H.]

The function of the predisposition gene to multiple endocrine neoplasia type 1 (MEN1) syndrome remains largely unknown. Previous studies demonstrated that null mutation of the Men1 gene caused mid-gestation lethality in mice, whereas heterozygous Men1 knockout mice developed multiple endocrine tumors late in life. To seek direct evidence on the causal role of menin in suppressing tumor development, we generated mice in which the Men1 gene was disrupted specifically in pancreatic ß cells. These mice began to develop hyperplastic islets at as early as 2 months of age and insulinomas at 6 months of age. The islet lesions exhibited features of multistage tumor progression, including ß-cell dedifferentiation, angiogenesis, and altered expression of both E-cadherin and ß-catenin. Additionally, disturbance of blood insulin and glucose levels correlated with tumor development, mimicking human MEN1 symptoms. Our data indicate that this strain of mice provides a powerful tool for the study of the mechanisms of tumorigenesis related to MEN1 disease.




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Copyright © 2003 by the American Association for Cancer Research.