VITAMIN-D DERIVATIVES INHIBIT THE MITOGENIC EFFECTS OF IGF-I ON MCF-7HUMAN BREAST-CANCER CELLS

The effects of 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) and four nov el synthetic analogues (EB1089, KH1060, KH1230 and CB1093) on IGF-I-st imulated growth of MCF-7 human breast cancer cells have been determine d. A significant time-and dose-dependent inhibition of IGF-I-stimulate d cell growth was seen with EB1089, such that after 7 days of treatmen t with 10(-8) M EB1089, the mitogenic effect of IGF-I (30 ng/ml) was n egated. Comparison with 1,25(OH)(2)D-3 showed the synthetic analogues to be more potent. The anti-oestrogen ICI 182,780 similarly inhibited IGF-I-stimulated growth of these cells and in combination with EB1089 exerted additional inhibitory effects. Retinoids (all-trans-retinoic a cid or the isomer 9-cis-retinoic acid) were less effective in Limiting MCF-7 cell responsiveness to IGF-I but, in combination with EB1089, a co-operative effect was achieved. Using radioligand-binding technique s, we observed that 1,25(OH)(2)D-3 and EB1089 down-regulated the level s of I-125-IGF-I binding to MCF-7 cell membranes. Scatchard analysis s howed that EB1089 decreased maximal binding approximately 2-fold. Vita min D derivatives were also demonstrated to reduce TGF-I receptor expr ession in MCF-7 cells by Western analysis. Our findings demonstrate th at vitamin D derivatives limit responsiveness of MCF-7 cells to the mi togenic effects of IGF-I, which may be mediated by reduction of IGF-I receptor expression.