Lack of augmentation of tumor spectrum or severity in dual heterozygous Men1 and Rb1 knockout mice

Abstract

To identify possible genetic interactions between the mechanisms of tumor suppression of menin and pRb, we intercrossed mice with targeted deletions of Men1 and Rb1, and compared tumor development in cohorts of animals carrying single or dual mutations of these tumorsuppressor genes. In mice lacking one copy of Men1, pancreatic islet and anterior pituitary adenomas are common. In animals lacking one copy of Rb1, intermediate pituitary and thyroid tumors occur at high frequency, with less frequent development of pancreatic islet hyperplasia and parathyroid lesions. In mice heterozygous for both Men1 and Rb1, pancreatic hyperplasia and tumors of the intermediate pituitary and thyroid occurred at high frequency. Serum measurements of calcium and glucose did not vary significantly between genotypic groups. Loss of heterozygosity at the Rb1 locus was common in pituitary and thyroid tumors, whereas loss of menin was observed in pancreatic and parathyroid lesions. The tumor spectrum in the double heterozygotes was a combination of pathologies seen in each of the individual heterozygotes, without decrease in age of onset, indicating independent, non-additive effects of the two mutations. Together with the lack of increased tumor spectrum, this suggests that menin and pRb function in a common pathway of tumor suppression.

Clinical and molecular genetics of acromegaly: MEN1, Carney complex, McCune–Albright syndrome, familial acromegaly and genetic defects in sporadic tumors

“…The tumor spectrum in compound heterozygotes presented with a combination of pathologies seen in each of the individual parental strains without a decrease in the age of onset, indicating independent, non-additive effects of the two mutations. The later is suggestive that menin and RB1 function in a common pathway of tumor suppression [111]. Other genes can modify these effects: loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1+/− animals by enhancing their differentiation [112].…”

“…Recent experiment on intercrosses of mice with targeted deletions of Men1 and Rb1 provided new data on the role that loss of RB1 plays in pituitary tumor development [111]. The tumor spectrum in compound heterozygotes presented with a combination of pathologies seen in each of the individual parental strains without a decrease in the age of onset, indicating independent, non-additive effects of the two mutations.…”

Menin and bone metabolism

“…Menin interacts with other bone-related factors, such as retinoblastoma protein, estrogen receptor, Hox and heat shock proteins, insulin-like growth factor-binding protein-2 and telomerase [5,53,54,[57][58][59][60][61]. Further studies on the interactions between menin and these factors in bone are necessary.…”

Exploring the Tumors of Multiple Endocrine Neoplasia Type 1 in Mouse Models for Basic and Preclinical Studies

“…Mice with knockout of the tumor suppressor p53 ( Trp53 +/− ) in an Men1 +/− background show independent and nonsynergistic effects on tumorigenesis, possibly indicating that disruption of the p53 pathway is not relevant for the endocrine tumors of MEN1 [43]. Menin partners with two similar multiprotein MLL-complexes, containing either MLL1 or MLL2 with an enzymatic activity (histone methyltransferase, HMTase) that catalyzes the trimethylation of histone H3 at lysine 4 [47,48].…”