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Primary hyperparathyroidism (PHPT) is a common endocrinopathy for which several pathogenic mechanisms, including cyclin D1 overexpression, have been identified. Vitamin D nutritional status may influence parathyroid tumorigenesis, but evidence remains circumstantial. To assess the potential influence of vitamin D insufficiency/deficiency on initiation or progression of parathyroid tumorigenesis, we superimposed vitamin D insufficiency or deficiency on parathyroid tumor–prone parathyroid hormone–cyclin D1 transgenic mice. Mice were placed on diets containing either 2.75 IU/g, 0.25 IU/g, or 0.05 IU/g cholecalciferol, either prior to expected onset of PHPT or after onset of biochemical PHPT. When introduced early, superimposed vitamin D insufficiency/deficiency had no effect on serum calcium or on parathyroid gland growth. However, when introduced after the onset of biochemical PHPT, vitamin D deficiency led to larger parathyroid glands without differences in serum biochemical parameters. Our results suggest that low vitamin D status enhances proliferation of parathyroid cells whose growth is already being tumorigenically driven, in contrast to its apparent lack of direct proliferation-initiating action on normally growing parathyroid cells in this model. These results are consistent with the hypothesis that suboptimal vitamin D status may not increase incidence of de novo parathyroid tumorigenesis but may accelerate growth of a preexisting parathyroid tumor.

The protein product of the cyclin D1 oncogene functions by activating partner cyclin-dependent kinases (cdk)4 or cdk6 to phosphorylate, thereby inactivating, the retinoblastoma protein pRB. Nonclassical, cdk-independent, functions of cyclin D1 have been described but their role in cyclin D1-driven neoplasia, with attendant implications for recently approved cdk4/6 chemotherapeutic inhibitors, requires further examination. We investigated whether cyclin D1's role in parathyroid tumorigenesis in vivo is effected primarily through kinase-dependent or kinase-independent mechanisms. Using a mouse model of cyclin D1-driven parathyroid tumorigenesis (PTH-D1), we generated new transgenic lines harboring a mutant cyclin D1 (KE) that is unable to activate its partner kinases. While this kinase-dead KE mutant effectively drove mammary tumorigenesis in an analogous model, parathyroid-overexpressed cyclin D1 KE mice did not develop the characteristic biochemical hyperparathyroidism or parathyroid hypercellularity of PTH-D1 mice. These results strongly suggest that in parathyroid cells, cyclin D1 drives tumorigenesis predominantly through cdk-dependent mechanisms, in marked contrast with the cdk-independence of cyclin D1-driven mouse mammary cancer. These findings highlight crucial tissue-specific mechanistic differences in cyclin D1-driven tumorigenesis, suggest that parathyroid/endocrine cells may be more tumorigenically vulnerable to acquired genetic perturbations in cdk-mediated proliferative control than other tissues, and carry important considerations for therapeutic intervention.