ANTIESTROGEN POTENTIATION OF ANTIPROLIFERATIVE EFFECTS OF VITAMIN-D-3ANALOGS IN BREAST-CANCER CELLS

[H-3]thymidine incorporation and DNA content were used to investigate the antiproliferative effects of 1,25(OH)(2)D-3 and four analogues [16 -ene-1,25(OH)(2)D-3 (16-ene)]; 16-ene,23-yne-1,25(OH)(2)D-3; EB1089; a nd 22 oxa-1,25(OH)(2)D-3] on MCF-7, BT-474, and MDA-MB-453 breast canc er cell lines. 1,25(OH)(2)D-3 and the analogues elicited a biphasic re sponse from MCF-7 and BT-474 estrogen receptor (ER)-positive cells, in the presence of estradiol (E(2)), with lower doses (between 10(-12) a nd 10(-10) M) tending to stimulate proliferation and higher doses (bet ween 10(-9) and 10(-6) M) inhibiting proliferation by as much as 65%. In the absence of E(2), the stimulatory effect was abrogated. Prolifer ation of MDA-MB-453, estrogen receptor-negative (ER(-)) cells, was sti mulated by these compounds only at 10(-12) M, and inhibited by all hig her doses, by as much as 83%. All three cell lines were shown to be vi tamin D receptor (VDR) positive, and 1,25(OH)(2)D-3 and all four analo gues bound to the VDR with high affinities in each cell line. The anti estrogen ICI 164,384 inhibited the proliferation of all three cell lin es. ICI 164,384 at 10(-8) M in combination with 1,25(OH)(2)D-3 or EB10 89 converted biphasic response of the ER(+) cells to one resembling th e response of the ER(-) cells, by eliminating the stimulatory response elicited by 1,25(OH)(2)D-3 at low doses and enhancing the antiprolife rative effects of higher doses by as much as 1000-fold. These data are consistent with the hypothesis that E(2) in the ER(+) cells blocks th e antiproliferative effects of the analogues and suggest the potential usefulness of combined antiestrogen and 1,25(OH)(2)D-3 analogues in E R(+) breast tumors, whereas 1,25(OH)(2)D-3 analogues alone might suffi ce in ER(-)breast tumors.