A Role for Interleukin-1 Alpha in the 1,25 Dihydroxyvitamin D3 Response in Mammary Epithelial Cells

Breast cancer is the most common non-cutaneous malignancy in American women, and better preventative strategies are needed. Epidemiological and laboratory studies point to vitamin D-3 as a promising chemopreventative agent for breast cancer. Vitamin D-3 metabolites induce anti-proliferative effects in breast cancer cells in vitro and in vivo, but few studies have investigated their effects in normal mammary epithelial cells. We hypothesized that 1,25(OH)(2)D-3, the metabolically active form of vitamin D-3, is growth suppressive in normal mouse mammary epithelial cells. In addition, we have previously established a role for the cytokine interleukin-1 alpha (IL1 alpha) in the anti-proliferative effects of 1,25(OH)(2)D-3 in normal prostate cells, and so we hypothesized that IL1 alpha is involved in the 1,25(OH)(2)D-3 response in mammary cells. Evaluation of cell viability, clonogenicity, senescence, and induction of cell cycle regulators p21 and p27 supported an anti-proliferative role for 1,25(OH)(2)D-3 in mammary epithelial cells. Furthermore, 1,25(OH)(2)D-3 increased the intracellular expression of IL1 alpha, which was necessary for the anti-proliferative effects of 1,25(OH)(2)D-3 in mammary cells. Together, these findings support the chemopreventative potential of vitamin D-3 in the mammary gland and present a role for IL1 alpha in regulation of mammary cell proliferation by 1,25(OH)(2)D-3.