Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder 
characterized by the combined occurrence of parathyroid and adrenocortical 
tumors, and neuroendocrine tumors (NETs) of the pancreas and pituitary. The 
pancreatic NETs are predominantly gastrinomas and insulinomas, and the pituitary 
NETs are mostly prolactinomas and somatotrophinomas. We postulated that the 
different types of pancreatic and pituitary NETs may be partly due to 
differences in their proliferation rates, and we therefore assessed these in 
MEN1-associated tumors and gonadal tumors that developed in mice deleted for an 
Men1 allele (Men1(+/-)). To label proliferating cells in vivo, Men1(+/-) and 
wild-type (Men1(+/+)) mice were given 5-bromo-2-deoxyuridine (BrdU) in drinking 
water from 1-12 wk, and tissue sections were immunostained using anti-BrdU and 
hormone-specific antibodies. Proliferation in the tumors of Men1(+/-) mice was 
significantly (P < 0.001) increased when compared with the corresponding normal 
Men1(+/+) tissues. Pancreatic, pituitary and adrenocortical proliferation fitted 
first- and second-order regression lines in Men1(+/+) tissues and Men1(+/-) 
tumors, respectively, R(2) = 0.999. Apoptosis was similar in Men1(+/-) 
pancreatic, pituitary, and parathyroid tumors when compared with corresponding 
normal tissues, decreased in Men1(+/-) adrenocortical tumors, but increased in 
Men1(+/-) gonadal tumors. Mathematical modeling of NET growth rates 
(proliferation minus apoptosis rates) predicted that in Men1(+/-) mice, only 
pancreatic β-cells, pituitary lactotrophs and somatotrophs could develop into 
tumors within a murine lifespan. Thus, our studies demonstrate that Men1(+/-) 
tumors have low proliferation rates (<2%), second-order kinetics, and the higher 
occurrence of insulinomas, prolactinomas, and somatotrophinomas in MEN1 is 
consistent with a mathematical model for NET proliferation.