EFFECTS OF A NEW SYNTHETIC VITAMIN-D ANALOG, EB1089, ON THE ESTROGEN-RESPONSIVE GROWTH OF HUMAN BREAST-CANCER CELLS

The anti-proliferative effects of the novel vitamin D analogue, EB1089 , were assessed in the hormone-dependent breast cancer cell line, MCF- 7, in vitro. In the present study, EB1089 was shown to be at least an order of magnitude more potent at inhibiting MCF-7 cell proliferation than the native hormone, 1 alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D -3). Treatment of MCF-7 cell cultures with combinations of oestradiol and EB1089 ranging from 5 x 10(-11) M to 5 x 10(-9) M revealed the abi lity of EB1089 to suppress the mitogenic effects of oestradiol in thes e cells dose-dependently, as determined by [H-3]thymidine incor porati on and cell counts. EB1089 also exhibited a significant time- and dose -dependent decrease in MCF-7 oestrogen receptor (ER) concentration, as assessed by Ligand binding assay. A fourfold reduction of ER levels b y 5 x 10(-9) M EB1089 relative to control ER levels was observed, whil st 5 x 10(-9) M 1,25(OH)(2)D-3 produced a significant but less dramati c decrease in ER levels. In addition, reduction of ER protein in EB108 9-treated cell cultures was also demonstrated using an oestrogen recep tor enzyme immunoassay. The interaction of EB1089 and anti-oestrogens on the oestradiol-stimulated growth of MCF-7 cells was investigated. T he treatment of cell cultures with 5 x 10(-10) M EB1089 in combination with the pure anti-oestrogen, ICI 182,780 (5 x 10(-8) M), and in the presence of between 5 x 10(-10) M and 5 x 10(-9) M oestradiol, produce d an augmented inhibition of MCF-7 cell proliferation compared with th e actions of either compound alone. This study demonstrates that EB108 9 is a potent anti-proliferative agent of breast cancer cells in vitro , and that part of its mechanism to inhibit cell growth may involve th e modulation of ER expression, such that the responsiveness of cells t o the growth-stimulatory effects of oestradiol is diminished. This new vitamin D analogue has potential in the treatment of breast cancer.