title: Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome.
abstract: The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by occurrence of parathyroid tumours, often atypical adenomas and carcinomas, ossifying jaw fibromas, renal tumours and uterine benign and malignant neoplasms. HPT-JT is caused by mutations of the cell division cycle 73 (CDC73) gene, located on chromosome 1q31.2 and encodes a 531 amino acid protein, parafibromin. To facilitate in vivo studies of Cdc73 in tumourigenesis we generated conventional (Cdc73+/-) and conditional parathyroid-specific (Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre) mouse models. Mice were aged to 18-21 months and studied for survival, tumour development and proliferation, and serum biochemistry, and compared to age-matched wild-type (Cdc73+/+and Cdc73+/+/PTH-Cre) littermates. Survival of Cdc73+/-mice, when compared to Cdc73+/+mice was reduced (Cdc73+/-=80%; Cdc73+/+=90% at 18 months of age, P<0.05). Cdc73+/-, Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre mice developed parathyroid tumours, which had nuclear pleomorphism, fibrous septation and increased galectin-3 expression, consistent with atypical parathyroid adenomas, from 9 months of age. Parathyroid tumours in Cdc73+/-, Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre mice had significantly increased proliferation, with rates >fourfold higher than that in parathyroid glands of wild-type littermates (P<0.0001). Cdc73+/-, Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre mice had higher mean serum calcium concentrations than wild-type littermates, and Cdc73+/-mice also had increased mean serum parathyroid hormone (PTH) concentrations. Parathyroid tumour development, and elevations in serum calcium and PTH, were similar in males and females. Cdc73+/-mice did not develop bone or renal tumours but female Cdc73+/-mice, at 18 months of age, had uterine neoplasms comprising squamous metaplasia, adenofibroma and adenomyoma. Uterine neoplasms, myometria and jaw bones of Cdc73+/-mice had increased proliferation rates that were 2-fold higher than in Cdc73+/+mice (P<0.05). Thus, our studies, which have established mouse models for parathyroid tumours and uterine neoplasms that develop in the HPT-JT syndrome, provide in vivo models for future studies of these tumours.
authors.affiliation: Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: G V
authors.initials: GV
authors.lastname: Walls
authors.affiliation: Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: M
authors.initials: M
authors.lastname: Stevenson
authors.affiliation: Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: K E
authors.initials: KE
authors.lastname: Lines
authors.affiliation: Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Newey
authors.affiliation: Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: A A C
authors.initials: AAC
authors.lastname: Reed
authors.affiliation: Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Bowl
authors.affiliation: Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Jeyabalan
authors.affiliation: Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: B
authors.initials: B
authors.lastname: Harding
authors.affiliation: Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Bradley
authors.affiliation: Department of Pathology, John Radcliffe Hospital, Headley Way, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Manek
authors.affiliation: Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: P
authors.initials: P
authors.lastname: Wang
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: B O
authors.initials: BO
authors.lastname: Williams
authors.affiliation: Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: R V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000236:Adenoma / Q000150:complications / Q000235:genetics*; D000818:Animals; D002277:Carcinoma / Q000150:complications / Q000235:genetics*; D005260:Female; D005350:Fibroma / Q000150:complications / Q000235:genetics*; D017353:Gene Deletion; D006961:Hyperparathyroidism / Q000150:complications / Q000235:genetics*; D007573:Jaw Neoplasms / Q000150:complications / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010282:Parathyroid Neoplasms / Q000150:complications / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014594:Uterine Neoplasms / Q000150:complications / Q000235:genetics*
chemical_list: C529591:HRPT2 protein, mouse; D025521:Tumor Suppressor Proteins