25-Hydroxyvitamin D3 is a natural chemopreventive agent against carcinogen induced precancerous lesions in mouse mammary gland organ culture
- 137 Downloads
Despite the role of vitamin D3 endocrine system in prevention of mammary gland transformation in animal models, use of 1,25(OH)2D3 in clinical settings is precluded due to its toxicity in vivo. Therefore much effort has been placed in developing relatively non-toxic vitamin D analogs. Recently, with the discovery of the expression of 25-hydroxy vitamin D3 1α-hydroxylase (CYP27B1) in multiple extrarenal organs, the functional role of prohormone, 25-hydroxyvitamin D3 [25(OH)D3], has been redefined. Since 25(OH)D3 does not cause hypercalcemia and maintains relative high concentration in serum, it is possible that the prohormone can be converted to active hormone in mammary epithelial cells to provide chemopreventive effects. In the present study, we evaluated its functional significance using mouse mammary organ culture (MMOC) system. We first showed that 25(OH)D3 1α-hydroxylase is extensively expressed in mammary ductal epithelial cells at both protein and mRNA levels, which is a prerequisite for 25(OH)D3 to function in an autocrine/paracrine manner. However, we also observed that clotrimazol (1α-hydroxylase inhibitor) enhanced 25(OH)D3 -induced CYP24 expression in breast cancer cells. In mammary glands derived from 1α-hydroxylase knockout mice, 25(OH)D3 treatment in organ culture significantly induced CYP24 expression, indicating a potential direct effect of 25(OH)D3. In MMOC, 100–250 nM 25(OH)D3 suppressed both ovarian hormone-dependent and -independent mammary precancerous lesions (induced by DMBA) by more than 50%, while the active hormone 1,25(OH)2D3 (positive control) at 100 nM suppressed alveolar lesions by more than 80%. The inactive vitamin D3 (negative control) at 100 nM suppressed alveolar lesions by only 20% (P > 0.05). We found that 25(OH)D3 inhibits DMBA-induced mammary alveolar lesions (MAL) in a stage-specific manner: 25(OH)D3 mainly inhibits the promotion stage of lesion formation. We conclude that 25(OH)D3 could serve as a non-toxic natural chemopreventive agent for further development for breast cancer prevention.
Keywords25(OH)D3 CYP27B1 Chemoprevention Precancerous lesions Mouse mammary gland organ culture (MMOC) CYP27B1KO mice CYP24
This work was supported by NIH Public Health Service Grant R03 CA121365-02 (XP) and R01 CA82316 (RGM). Support for engineering of the CYP27B1K0 mice was provided by a grant from shriners of North America to R. St-Arnaud.
- 1.Berry DM, Meckling-Gill KA (1999) Vitamin D analogs, 20-Epi-22-oxa-24a,26a,27a,-trihomo-1alpha,25(OH)2-vitamin D3, 1,24(OH)2-22-ene-24-cyclopropyl-vitamin D3 and 1alpha,25(OH)2-lumisterol3 prime NB4 leukemia cells for monocytic differentiation via nongenomic signaling pathways, involving calcium and calpain. Endocrinology 140:4779–4788PubMedCrossRefGoogle Scholar
- 9.Lipkin M, Newmark HL (1999) Vitamin D, calcium and prevention of breast cancer: a review. J Am Coll Nutr 8:392S–397SGoogle Scholar
- 40.Nykjaer A, Fyfe JC, Kozyraki R, Leheste JR, Jacobsen C, Nielsen MS, Verroust PJ, Aminoff M, de la Chapelle A, Moestrup SK, Ray R, Gliemann J, Willnow TE, Christensen EI. (2001) Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Proc Natl Acad Sci USA 98:13895–13900PubMedCrossRefGoogle Scholar