Journal Article

Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome

Teh, B T, Jeyabalan, J, Harding, B, Thakker, R V, Newey, P J, Bradley, K J, Stevenson, M, Lines, K E, Manek, S, Chen, J, Williams, B O, Wang, P, Bowl, M R, Walls, G V, Reed, A A C

2017

Overview

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 Cdc73 L/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 Cdc73 L/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 Cdc73 L/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 Cdc73 L/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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 14/63 / 631/1647/334 / 631/208/68 / 631/67/1459 / 631/67/70 / 64/110 / Adenoma - complications / Adenoma - genetics / Age / Animal models / Animals / Apoptosis / Benign / Biochemistry / Bone tumors / Calcium / Calcium (blood) / Carcinoma / Carcinoma - complications / Carcinoma - genetics / Cell Biology / Cell division / Chromosome 1 / Development and progression / Female / Fibroma - complications / Fibroma - genetics / Galectin-3 / Gene Deletion / Genetic aspects / Glands / Hereditary diseases / Human Genetics / Hyperparathyroidism / Hyperparathyroidism - complications / Hyperparathyroidism - genetics / Internal Medicine / Jaw / Jaw Neoplasms - complications / Jaw Neoplasms - genetics / Kidneys / Male / Medicine / Medicine & Public Health / Metaplasia / Mice / Mice, Inbred C57BL / Mice, Knockout / Neuroendocrine tumors / Oncology / Original / original-article / Parathyroid / Parathyroid hormone / Parathyroid Neoplasms - complications / Parathyroid Neoplasms - genetics / Pleomorphism / Rodents / Septation / Survival / Thyroid gland / Tumor Suppressor Proteins - genetics / Tumorigenesis / Tumors / Uterine cancer / Uterine Neoplasms - complications / Uterine Neoplasms - genetics / Uterine tumors / Uterus / Vitamin D