Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by the occurrence of multiple endocrine
tumors of the parathyroid, pancreas, and anterior pituitary in patients. To study
tumorigenesis related to the MEN1 syndrome, we have generated Men1 knockout mice using the gene targeting approach. Heterozygous Men1 mutant mice developed the same range of major endocrine
tumors as is seen in MEN1 patients, affecting the parathyroid, pancreatic islets, pituitary and adrenal glands, as well as the thyroid, and exhibiting multistage
tumor progression with metastatic potential. In particular, extrapancreatic
gastrinoma, pancreatic
glucagonoma, and mixed
hormone-producing
tumors in islets were observed. In addition, there was a high incidence of gonadal
tumors of endocrine origin, i.e. Leydig cell
tumors, and ovary sex-cord stromal cell
tumors in heterozygous Men1 mutant mice. Hormonal disturbance, such as abnormal PTH and
insulin levels, was also observed in these mice. These
tumors were associated with loss of heterozygosity of the wild-type Men1 allele, suggesting that menin is involved in suppressing the development of these endocrine
tumors. All of these features are reminiscent of MEN1 symptoms in humans and establish heterozygous Men1 mutant mice as a suitable model for this disease.