INHIBITION OF INSULIN AND INSULIN-LIKE GROWTH-FACTOR-I-STIMULATED GROWTH OF HUMAN BREAST-CANCER CELLS BY 1,25-DIHYDROXYVITAMIN-D-3 AND THE VITAMIN-D-3 ANALOG-EB1089

1,25 Dihydroxyvitamin D-3 (1,25-(OH)(2)D-3) and a number of synthetic vitamin D-3 analogues with low calcaemic activity, have been shown to inhibit breast cancer cell growth in vitro as well as in vivo. The pur pose of the present study was to investigate a possible interaction of 1, 25-(OH)(2)D-3 and the vitamin D-3 analogue EB1089 with the insulin -IGF-I regulatory system. The oestrogen receptor-positive MCF-7 human breast cancer cells used in this study are able to grow autonomously a nd their growth is stimulated by insulin. In order to avoid interferen ce of IGF-binding proteins (IGF-BPs), we used an analogue of IGF-I, lo ng R(3) IGF-I, which stimulated MCF-7 cell growth similar to insulin. The growth stimulation by insulin and by long R(3) IGF-T was completel y inhibited by 1,25-(OH)(2)D-3 and EB1089. Autonomous growth was also inhibited by 1,25-(OH)(2)D-3 and EB1089. The analogue EB1089 was activ e at 50 times lower concentrations than 1,25-(OH)(2)D-3. It was shown that growth inhibition was not achieved through downregulation of insu lin and IGF-I binding after 48 h. Paradoxically, after prolonged treat ment (8 days), an upregulation of insulin and IGF-I binding was observ ed. Two possible intracellular mediators of the insulin-IGF mitogenic signal are C-FOS and mitogen-activated protein (MAP) kinase. Insulin-i nduced C-FOS mRNA was inhibited by 1,25-(OH)(2)D-3, suggesting that it could be involved in the growth inhibition by 1,25-(OH)(2)D-3. MAP ki nase activation appeared not to be involved in growth stimulation by b oth insulin and IGF-I. Together, the present study demonstrates that v itamin D-3 compounds can block the mitogenic activity of insulin and I GF-I, which may contribute to their tumour suppressive activity observ ed in vivo. Copyright (C) 1996 Elsevier Science Ltd