1,25-dihydroxyvitamin D3 and retonic acid analogues induce differentiation in breast cancer cells with function- and cell-specific additive effects

Vitamin D-3 derivatives and retinoids can induce cell cycle arrest, differentiation and cell death in many cell lines. These compounds can act cooperatively in some of their functions and may be of potential use either individually or in combination in the treatment of breast cancer. The effects of 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), all-trans retinoic acid (ATRA) and several analogues were evaluated on malignant phenotypic traits of breast cancer cell lines MCF-7, T-47D and MDA-MB-231. Both 1,25(OH)(2)D-3 and ATRA caused a decrease in anchorage independent colony formation in MCF-7 and T-47D cells in a dose-dependent manner. The effects of 1,25(OH)(2)D-3 10(-10) and 10(-9) M were synergistic with ATRA 10(-8) M in T-47D cells but were antagonistic in both MCF-7 and in T-47D cells at most concentrations. Both 1,25(OH)(2)D-3 and ATRA individually induced an accumulation of MCF-7 cells in the G(1) phase of the cell cycle and an associated increase in p21(WAF1/Cip1), p27(Kip1) and a dephosphorylation of Rb but the effects were not additive. Both compounds inhibited the invasive capacity of MDA-MB-231 cells. 1,25(OH)(2)D-3 but not ATRA caused an increase in E-cadherin levels in MDA-MB-231 cells. These two functions were not additive. The compounds 1,25(OH)(2)D-3, a noncalcemic analogue 1,25(OH)(2)-16-ene-23-yne-D-3, ATRA, AGN195183, an RAR alpha -specific agonist, and AGN190168 (tazarotene), an RAR beta/gamma -selective agonist, induced differentiation as determined by measurements of lipid droplet formation. The individual effects of 1,25(OH)(2)-16-ene-23-yne-D-3 combined with ATRA or with tazarotene at 10(-9) M each were additive in MCF-7 and MDA-MB-231 cells on lipid formation. The data demonstrate that both 1,25(OH)(2)D-3, ATRA, and selected analogues induce a more differentiated phenotype in breast cancer cells with additive effects that are function- and cell-specific.