Mutations of the cell division cycle 73 (CDC73) gene, which encodes the 531 amino acid protein parafibromin, are associated with the Hyperparathyroidism-Jaw Tumour (HPT-JT) syndrome, an autosomal dominant disorder characterised by parathyroid tumours and ossifying jaw fibromas. In addition, ∼75% of women with HPT-JT develop benign and malignant uterine tumours, which include endometrial hyperplasia, adenosarcomas, adenofibromas, and leiomyomas. To explore the role of CDC73 in uterine tumourigenesis, we developed a mouse model deleted for one Cdc73 allele (Cdc73+/−). Mice were kept in accordance with welfare guidelines and project licence restrictions. Female Cdc73+/− and wild-type (Cdc73+/+) mice were studied at ≧18 months of age, and proliferation was assessed by administration of five-bromo-two-deoxyuridine in drinking water for two weeks. Uterine tumours, which included adenofibromas and adenomyomas developed in 33% of Cdc73+/− mice (8 of 24 mice), but in none of 23 wild-type littermates. These Cdc73+/− mice also had several other endometrial histological abnormalities which included: large wall cysts; hyperplasia with squamous metaplasia; and transluminal bridging. Furthermore, immunohistochemistry demonstrated reduced parafibromin expression and loss of progesterone receptor expression in the uterine hyperplasia and tumours of these Cdc73+/− mice, when compared to that in normal uteri from Cdc73+/+ mice. In addition, proliferation rates in uterine myometria from Cdc73+/− mice were significantly increased compared to myometria from Cdc73+/+ littermates (0.900±0.168% vs 0.526±0.063%, respectively, P<0.05). Thus, one third of female Cdc73+/− mice developed uterine hyperplasia and tumours with reduced parafibromin expression, loss of progesterone receptor expression, and increased cellular proliferation rates. These female Cdc73+/− mice may therefore provide a useful model for the study of aetiological molecular mechanisms and treatments for uterine tumours.
Declaration of funding
This work was supported by the United Kingdom Medical Research Council (grant numbers G9825289, 2004 and G1000467, 2010) and the United Kingdom National Institute of Health Research.