It has been previously demonstrated that 1,25 dihydroxyvitamin D(3) (1,25-D(3)) exerts inhibitory effects in breast cancer cells. The aim of this study was to determine whether mitogen-activated protein kinase (MAPK) pathways are associated with 1,25-D(3)-induced cell death in breast cancer. We used three breast cell lines which have different sensitivities to 1,25-D(3) treatment. Non-malignant MCF-12A cells were more sensitive to 1,25-D(3) treatment than malignant MCF-7 cells (growth inhibition IC(50) 75 nM vs. 100 nM, p<0.001) while malignant MDA-MB-231 cells were resistant. Moreover, 1,25-D(3)-induced apoptosis was caspase-dependent in MCF-12A cells and caspase-independent in MCF-7 cells. Following MAPK activation analysis, we found a significant activation of JNK in MCF-12A cells and malignant MCF-7 cells in response to 1,25-D(3) treatment. Furthermore, 1,25-D(3) treatment stimulated p38 activity in MCF-12A cells and in MCF-7 cells. ERK1/2 activity was unaffected by 1,25-D(3) treatment in all breast cells. Importantly, no increased MAPK activity was observed in MDA-MB-231 breast cancer cells which displayed resistance to 1,25-D(3)-induced apoptosis. Utilising specific pharmacological inhibitors of JNK and p38, it was demonstrated that MCF-12A and MCF-7 cells were protected from death induced by 1,25-D(3). These results implicate JNK and p38 signalling in 1,25-D(3)-induced cancer breast cell death.
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