1,25-dihydroxyvitamin D-3 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, differe ntiation and cell death in many cell lines. These compounds can act coopera tively in some of their functions and may be of potential use either indivi dually 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 brea st cancer cell lines MCF-7, T-47D and MDA-MB-231. Both 1,25(OH)(2)D-3 and A TRA caused a decrease in anchorage independent colony formation in MCF-7 an d 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 we re antagonistic in both MCF-7 and in T-47D cells at most concentrations. Bo th 1,25(OH)(2)D-3 and ATRA individually induced an accumulation of MCF-7 ce lls in the G(1) phase of the cell cycle and an associated increase in p21(W AF1/Cip1), p27(Kip1) and a dephosphorylation of Rb but the effects were not additive. Both compounds inhibited the invasive capacity of MDA-MB-231 cel ls. 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, AGN 195183, an RAR alpha -specific agonist, and AGN190168 (tazarotene), an RAR beta/gamma -selective agonist, induced differentiation as determined by mea surements 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 w ere additive in MCF-7 and MDA-MB-231 cells on lipid formation. The data dem onstrate that both 1,25(OH)(2)D-3, ATRA, and selected analogues induce a mo re differentiated phenotype in breast cancer cells with additive effects th at are function- and cell-specific.