在转基因小鼠中,CDC73 缺失并不增强 cyclin D1 驱动的甲状旁腺肿瘤发生

Loss-of-function mutations in the CDC73 tumor suppressor gene, encoding parafibromin, are the most common genetic alteration in parathyroid carcinoma. Germline CDC73 mutation causes Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT), a rare tumor predisposition syndrome including parathyroid carcinoma, and both germline and somatic CDC73 mutations are seen in patients with sporadically presenting parathyroid cancer. Oncogenic amplification of CCND1 , which encodes cyclin D1, is another frequent finding in parathyroid carcinoma. Parathyroid-targeted overexpression, via a PTH-cyclin D1 (PCD) transgene, leads to parathyroid tumorigenesis, but not parathyroid malignancy, in transgenic mice. The absence of appropriate preclinical models has hindered the development of preventative strategies for patients with germline CDC73 mutation and of non-surgical treatments for parathyroid cancer in general. Thus, we sought to develop a model system that could mimic the clinical course of CDC73 /parafibromin-deficient parathyroid carcinoma, including robust parathyroid hormone (PTH)-dependent hypercalcemia and invasion/metastasis. To this end, we crossed parathyroid-targeted CDC73 null mice with PCD transgenic mice, producing offspring with both CDC73 deficiency and cyclin D1 overexpression in parathyroid cells. Double mutant mice were compared to PCD mice and wildtype littermate controls. Mice were monitored for the progression of parathyroid tumorigenesis by monthly blood collection and evaluation of serum calcium and PTH. Mice were euthanized at 18 months of age. The parathyroid glands and surrounding tissue were dissected en bloc and evaluated histologically for general morphology, local invasion, and parathyroid cell proliferation via Ki-67 immunostaining. While PCD-positive mice developed hypercalcemia, a hallmark of parathyroid tumorigenesis, as expected, no significant differences in calcium levels were observed between mice with both CDC73 deficiency and cyclin D1 overexpression as compared to mice with cyclin D1 overexpression alone. Similarly, general parathyroid gland morphology and parathyroid cell proliferation were comparable between the two groups; local tumor invasion was not observed in either group. While the combined disruption of Cdc73 and the overexpression of cyclin D1 did not result in the development of parathyroid carcinoma in our mouse model, this model system may provide valuable insight into genetic modifiers of parathyroid tumorigenesis. Background strain is known to affect the phenotype of many genetically modified mouse models, including parathyroid-targeted Cdc73 deletion; however, the responsible genetic modifiers remain unknown. Our model system could serve as a key reagent in identifying genetic modifiers with relevance to parathyroid tumor development.