Journal
ONCOGENE
Volume 36, Issue 28, Pages 4025-4036Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2017.43
Keywords
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Funding
- Medical Research Council (MRC), UK [G9825289/2004, G1000467/2010]
- Van Andel Foundation, Grand Rapids, USA
- United Kingdom Medical Research Council (MRC) [G9825289, G1000467]
- MRC [G1000467, G9825289] Funding Source: UKRI
- Medical Research Council [G1000467, G9825289] Funding Source: researchfish
- National Institute for Health Research [CL-2010-13-004] Funding Source: researchfish
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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 4fourfold 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. Cdc7(3+)/-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.
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