Abstract 1842: Vitamin D compounds induce BRCA1 expression and inhibit breast stem cells

Background: Basal breast cancer which occurs in women with BRCA1 mutations has been suggested to arise from arrested differentiation of stem/luminal progenitor cells, whose gene profile includes Vitamin D receptor prominently. In addition to DNA repair, BRCA1 enhances luminal differentiation of breast stem cells. Vitamin D compounds have long been known to have differentiating function. We hypothesized that Vitamin D receptor exists on stem cells and that vitamin D treatment induces differentiation of stem/progenitor cells, in part due to increased BRCA1 expression. Methods: We treated normal human breast epithelial cells and MCF-7 breast cancer cells with 10 or 100 nM 1, 25 dihydroxyvitamin D3 or the less hypercalcemic vitamin D5 analogue (1alpha(OH)D5) in suspension culture in stem cell media to assess: 1) stem cell self renewal using the mammosphere assay; 2) inhibition of stem cell percentage; 3) induction of BRCA1 mRNA and 4) induction of BRCA1 protein. Results: Teatment with 100nM 1alpha(OH)D5 inhibited stem cell self renewal as assessed by mammosphere formation assay from 23spheres/high power field (HPF) to 1 per HPF at 7 days; inhibited of percentage of stem cells from 17% in vehicle control to 7% with vitamin D5. Both vitamin D3 and D5 caused an 8 fold induction of vitamin D target CYP24 gene expression; 4 fold increase in BRCA1 mRNA by real time PCR; and 4 fold increase in BRCA1 protein expression by western blot compared to actin control. Conclusion: Vitamin D3 and D5 analogue induce BRCA1 expression and inhibit stem cell percentage in normal breast cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1842. doi:10.1158/1538-7445.AM2011-1842