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Vitamin D analogs are effective inhibitors of breast cancer cell growth, but many breast cancer cell lines show various degrees of resistance to the growth inhibitory effect of vitamin D. In this study, we investigated the mechanism of 1,25-dihydroxyvitamin D 3  [1,25(OH) 2 D 3 ] resistance of the human breast epithelial cell line HBL100, which had been immortalized by Simian virus 40 (SV40) large T antigen. We determined the expression, DNA binding and transactivation activity of vitamin D 3  receptor (VDR) in HBL100 and a vitamin D-sensitive ZR75-1 breast cancer cell line. Western blot analysis revealed a comparable expression of VDR gene in both cell lines. However, gel retardation assays demonstrated nuclear proteins from ZR75-1 cells but not from HBL100; cells expressed a 9-fold increase in the binding activity with a vitamin D response element (VDRE). Using a transient transfection assay, we showed that the VDRE was activated by 8-fold in ZR75-1. However, in HBL100 cells there was no activation observed in response to 1,25(OH) 2 D 3 . On the other hand, co-transfection of a VDR expression vector could restore 1,25(OH) 2 D 3 -induced VDRE transcription in HBL100 cells. Moreover, stable expression of VDR in HBL100 cells resulted in enhanced sensitivity of the cells to the growth inhibitory effect of 1,25(OH) 2 D 3 . Since CV-1 cells express very little endogenous VDR, the interactions of VDR and large T antigen were carried out in these cells. By transient co-transfection, we observed that expression of the large T antigen strongly inhibited 1,25(OH) 2 D 3 -induced VDRE transcriptional activity in a dose-dependent fashion in CV-1 cells. At 120 ng VDR concentration, the inhibition was completely reversed. Thus the loss of the growth inhibitory effect of vitamin D 3  in HBL100 cells may be caused by the expression of the large T antigen in the cells, and provide further evidence that VDR is required for efficient growth inhibition by vitamin D 3 .

Resistance of HBL100 human breast epithelial cells to vitamin D action