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

Gerard V. Walls, Mark Stevenson, K E Lines, P J Newey, A A C Reed, Michael R. Bowl, Jeshmi Jeyabalan, Brian Harding, K J Bradley, Sanjiv Manek, J Chen, P. Z. Wang, B O Williams, B. T. Teh, Rajesh V. Thakker

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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 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.

Original languageEnglish
Pages (from-to)4025-4036
Number of pages12
JournalOncogene
Volume36
Issue number28
DOIs
Publication statusPublished - 13 Jul 2017

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    Walls, G. V., Stevenson, M., Lines, K. E., Newey, P. J., Reed, A. A. C., Bowl, M. R., Jeyabalan, J., Harding, B., Bradley, K. J., Manek, S., Chen, J., Wang, P. Z., Williams, B. O., Teh, B. T., & Thakker, R. V. (2017). Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome. Oncogene, 36(28), 4025-4036. https://doi.org/10.1038/onc.2017.43