Vitamin D and Breast Cancer

Vitamin D regulates calcium and phosphorus blood levels and bone metabolism via effects on intestine, kidney, and bone. Vitamin D is formed from 7-dehydrocholesterol in the skin by ultraviolet irradiation or is taken up from dietary sources. Vitamin D must be metabolically altered successively in the liver and kidney to form the biologically most active compound, 1,25-dihydroxyvitamin D3. This active compound acts through binding to a specific receptor, the vitamin D receptor, which is a member of the steroid hormone receptor family. During the last fifteen years, it has become apparent that the active form of vitamin D exerts effects on a variety of tissues apparently unrelated to calcium homeostasis. 1,25-Dihydroxyvitamin D3 has been shown to promote cellular differentiation and inhibit proliferation of haematopoietic cells, cancer cells, and keratinocytes. In addition, studies with animal models for cancer have shown that 1,25-dihydroxyvitamin D3 administration can prolong the survival of leukaemic mice and suppress the growth of tumours of different origin, including breast, colon, skin, and lung. This thesis focuses on a possible role of vitamin D in the treatment of breast cancer

Inhibition of insulin- and insulin-like growth factor-I-stimulated growth of human breast cancer cells by 1,25-dihydroxyvitamin D3 and the vitamin D3 analogue EB1089

1, 25 Dihydroxyvitamin D3 (1,25-(OH)2D3) and a number of synthetic vitamin D3 analogues with low calcaemic activity, have been shown to inhibit breast cancer cell growth in vitro as well as in vivo. The purpose of the present study was to investigate a possible interaction of 1, 25-(OH)2D3 and the vitamin D3 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 and their growth is stimulated by insulin. In order to avoid interference of IGF-binding proteins (IGF-BPs), we used an analogue of IGF-I, long R3 IGF-I, which stimulated MCF-7 cell growth similar to insulin. The growth stimulation by insulin and by long R3 IGF-I was completely inhibited by 1,25-(OH)2D3 and EB1089. Autonomous growth was also inhibited by 1,25-(OH)2D3 and EB1089. The analogue EB1089 was active at 50 times lower concentrations than 1,25-(OH)2D3. It was shown that growth inhibition was not achieved through downregulation of insulin and IGF-I binding after 48 h. Paradoxically, after prolonged treatment (8 days), an upregulation of insulin and IGF-I binding was observed. Two possible intracellular mediators of the insulin-IGF mitogenic signal are C-FOS and mitogen-activated protein (MAP) kinase. Insulin-induced C-FOS mRNA was inhibited by 1,25-(OH)2D3, suggesting that it could be involved in the growth inhibition by 1,25-(OH)2D3. MAP kinase activation appeared not to be involved in growth stimulation by both insulin and IGF-I. Together, the present study demonstrates that vitamin D3 compounds can block the mitogenic activity of insulin and IGF-I, which may contribute to their tumour suppressive activity observed in vivo. Copyrigh