Regulation of Vitamin D Receptor by 1,25-dihydroxyvitamin D in Breast Cancer (P05-013-19)

Abstract

ObjectivesLoss of vitamin D receptor (VDR) is reported during tumor progression in cancer cells, including breast cancer, with the implication that vitamin D may not be effective in inhibiting metastasis. The purpose of these studies was to investigate the expression and activity of the VDR in breast cancer cells at different stages of progression and the response to treatment with the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D). We hypothesized that although constitutive expression of VDR is downregulated during cancer progression, 1,25(OH)2D induces an increase in VDR transcriptional activity and VDR expression in metastatic breast cancer cells. MethodsWe employed a series of human cells representing different stages of breast cancer, the MCF-10A series which includes untransformed MCF10A, Harvey-ras oncogene transfected early progression model (MCF10A-ras), and metastatic MCF10CA1a cells. Cells were treated with 1,25(OH)2D (10 nM) or vehicle for 2 and 5 days. VDR mRNA expression was measured by PCR and VDR transcriptional activity by mRNA expression of CYP24. ResultsConstitutive VDR mRNA expression was reduced by 76% in metastatic MCF10CA1a compared to untransformed MCF10A. Treatment with 1,25(OH)2D for 5 days decreased VDR mRNA expression in MCF10A (43%) and MCF10A-ras (37%) cells compared to vehicle treatment. In contrast, treatment with 1,25(OH)2D for 5 days increased VDR mRNA expression by 61% in metastatic MCF10CA1a cells. In addition, VDR transcriptional specific activity increased in MCF10A-ras cell and trended towards an increase (P = 0.06) in MCF10CA1a cells compared to MCF10A, as assessed by measuring the ratio of CYP24/VDR mRNA expression. ConclusionsTaken together, these results suggest that although constitutive expression of VDR is reduced in metastatic cells, vitamin D may exert inhibitory effects through 1,25(OH)2D upregulation of VDR expression and activity in breast cancer. Funding SourcesSupport from National Institute of Health and USDA.