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

TY - JOUR

T1 - Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours

T2 - model for the hyperparathyroidism-jaw tumour syndrome

AU - Walls, Gerard V.

AU - Stevenson, Mark

AU - Lines, K E

AU - Newey, P J

AU - Reed, A A C

AU - Bowl, Michael R.

AU - Jeyabalan, Jeshmi

AU - Harding, Brian

AU - Bradley, K J

AU - Manek, Sanjiv

AU - Chen, J

AU - Wang, P. Z.

AU - Williams, B O

AU - Teh, B. T.

AU - Thakker, Rajesh V.

N1 - This work was supported by the Medical Research Council (MRC), UK (grant number G9825289/2004 and G1000467/2010), (GV Walls, M Stevenson, KE Lines, MR Bowl, J Jeyabalan, PJ Newey, AAC Reed, B Harding, KJ Bradley and RV Thakker), and the Van Andel Foundation, Grand Rapids, USA (P Wang, J Chen, BO Williams, BT Teh). GV Walls, PJ Newey and KJ Bradley received MRC Clinical Research Training Fellowships. This work was supported by grants from the United Kingdom Medical Research Council (MRC) (G9825289 and G1000467) to GVW, MS, KEL, PJN, AACR, MRB, JJ, BH, KJB, and RVT; and the Van Andel Foundation, Grand Rapids, USA to JC, PW, BOW and BTT.

PY - 2017/7/13

Y1 - 2017/7/13

N2 - 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.

AB - 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.

U2 - 10.1038/onc.2017.43

DO - 10.1038/onc.2017.43

M3 - Article

C2 - 28288139

SN - 0950-9232

VL - 36

SP - 4025

EP - 4036

JO - Oncogene

JF - Oncogene

IS - 28

ER -