Protection against cellular stress by 25-hydroxyvitamin D3 in breast epithelial cells.

25-Hydroxyvitamin D(3) (25(OH)D(3)) is a prohormone and a major vitamin D metabolite. The discovery of (25(OH)D(3)) 1 alpha-hydroxylase in many vitamin D target organs has yielded an increased interest in defining the role(s) of 25(OH)D(3) in these tissues. The etiology of cancer appears to be complex and multi-factorial. Cellular stress (e.g., DNA damage, hypoxia, oncogene activation) has been identified as one of the key factors responsible for initiating the carcinogenesis process. In this study, we investigated whether 25(OH)D(3) protects breast epithelial cells from cellular stress using an established breast epithelial cell line MCF12F. To better elucidate the role of 25(OH)D(3) in the stress response, we used multiple in vitro stress models including serum starvation, hypoxia, oxidative stress, and apoptosis induction. Under all these stress conditions, 25(OH)D(3) (250 nmol/L) treatment significantly protected cells against cell death. Low-serum stress induced p53 expression accompanied with downregulation of PCNA, the presence of 25(OH)D(3) consistently inhibited the alteration of p53 and PCNA, suggesting that these molecules were involved in the stress process and may be potential target genes of 25(OH)D(3). miRNA microarray analysis demonstrated that stress induced by serum starvation caused significant alteration in the expression of multiple miRNAs including miR182, but the presence of 25(OH)D(3) effectively reversed this alteration. These data suggest that there is a significant protective role for 25(OH)D(3) against cellular stress in the breast epithelial cells and these effects may be mediated by altered miRNA expression.