Functions of 1alpha,25-dihydroxyvitamin D(3) in mammary gland: from normal development to breast cancer.

This review examines the role of 1alpha,25(OH)(2)D(3) (1,25D) and the vitamin D(3) receptor in growth regulation of normal and transformed mammary epithelial cells. 1,25D exerts both anti-proliferative and pro-apoptotic functions in transformed mammary cells such as MCF-7. The anti-proliferative effects of 1,25D have been linked to suppression of growth stimulatory signals and potentiation of growth inhibitory signals, which lead to changes in cell cycle regulators such as p21, p27, cyclins and Rb. The pro-apoptotic effects of 1,25D involve alterations in the relative ratios of the bcl-2 family members which regulate mitochondrial integrity. In MCF-7 human breast cancer cells, 1,25D mediated apoptosis is associated with translocation of the pro-apoptotic protein Bax to the mitochondria, generation of reactive oxygen species, dissipation of the mitochondrial membrane potential and release of cytochrome c. These mitochondrial events trigger apoptosis in a caspase-independent manner, since caspase inhibitors do not rescue 1,25D treated cells from death. The potential role of 1,25D in growth and differentiation of normal mammary epithelial cells has been examined in VDR null mice. Initial data indicates a significant decrease in ductal differentiation in VDR null mice compared to age matched wild type mice, reflected as an increased number of undifferentiated terminal end buds in the VDR null mouse. These data suggest that 1,25D promotes differentiation during early mammary gland development. In summary, our studies suggest an expanding role for the vitamin D(3) endocrine system in control of proliferation, differentiation and apoptosis of mammary epithelial cells.