MOLECULAR, NUTRIENT, AND ENDOCRINE BASIS OF METABOLIC DISEASES THAT AFFECT THE REPRODUCTIVE HEALTH OF THE DAIRY COW
Location: Ruminant Diseases and Immunology Research Unit
Title: Vitamin D delays breast cancer progression in the PyVMT transgenic mouse model: local conversion of the precursor 25(OH)D3 into 1,25(OH)2D3 is safer and more effective than systemic administration of 1,25(OH)2D3
| Rossdeutscher, L - MCGILL UNIVERSITY |
| Huang, D - MCGILL UNIVERSITY |
| Li, J - MCGILL UNIVERSITY |
| Muller, W - MCGILL UNIVERSITY |
| Kremer, R - MCGILL UNIVERSITY |
Submitted to: American Society for Bone and Mineral Research
Publication Type: Abstract Only
Publication Acceptance Date: August 29, 2008
Publication Date: September 12, 2008
Citation: Rossdeutscher, L., Huang, D., Li, J., Reinhardt, T.A., Muller, W., Kremer, R. 2008. Vitamin D delays breast cancer progression in the PyVMT transgenic mouse model: local conversion of the precursor 25(OH)D3 into 1,25(OH)2D3 is safer and more effective than systemic administration of 1,25(OH)2D3 [abstract]. Journal of Bone and Mineral Research. 23(abstracts supplement):S53.
Metabolic activation of 1,25(OH)2D3 occurs at extra renal sites in several organs, including the breast. The purpose of this study was to determine if this local tumoral 25OHD3-1alphahydroxylase expression modulates any or all of the stages of breast tumor progression. For this purpose we used the PyVMT breast cancer mouse model in which the oncoprotein, polyomamiddle T antigen (PyMT) is under the control of mouse mammary tumor virus LTR (MMTV LTR) and faithfully reproduces all stages of human breast cancer. Four-week-old females were treated prior to mammary intraepithelial neoplasia with either vehicle, 25OHD3 (2000 pM/24 h) or 1,25(OH)2D3 (12 pM/24 h) for a total of 8 weeks. 1alphahydroxylase expression was measured and remained unchanged throughout the various stages of tumor progression. Kaplan Meier analysis indicated that mice treated with 25OHD3 or 1,25(OH)2D3 had a significant delay in tumor onset as compared to vehicle-treated animals (25OHD3 = 27 days > 1,25(OH2D3 = 23 days > Control = 9 days, P < .05). Furthermore, tumor growth over time was significantly reduced in both 25OHD3 and 1,25(OH)2D3 treated groups in comparison to the placebo-treated group (25OHD3 58.0 +/- 2.0% (P < .002) > 1,25(OH)2D3 45.1 +/- 2.2% (P < .002) > Control). In addition, the expression of biomarkers and histological indices of tumor progression in 25OHD3 and 1,25(OH)2D3 treated animals were markedly delayed as compared to vehicle-treated animals. However, mean circulating 1,25(OH)2D3 and calcium concentrations remained unchanged in 25OHD3-treated animals (2.39 +/- .1 mmol/L) but increased significantly in 1,25(OH)2D3-treated animals (3.19 +/- .09 mmol/L P < .05) as compared to vehicle-treated (2.38 +/- .02 mmol/L). Moreover, tumoral levels of 1,25(OH)2D3 in mice treated with 25OHD3 were significantly higher as compared to both 1,25(OH)2D3 and vehicle-treated animals (25OHD3 = 390 +/- 16.7 pg/g > 1,25(OH2D3 = 326 +/- .26.8 pg/g > Control = 182 +/- .10.5 pg/g, P < .05). Finally, 25OHD3 and 1,25(OH)2D3-treated animals had a significant decrease in the mean number and surface area of lung metastases as compared to vehicle-treated animals (P < .05). Our data indicate that metabolic activation of 25OHD3 in the mammary epithelium delays tumor progression and is more potent than systemic administration of 1,25(OH)2D3 without inducing significant side effects. Our data suggest that strategies aimed at increasing local tissue concentrations of 1,25(OH)2D3 may provide a novel and safe approach in the prevention of breast cancer.