COMBINED EFFECTS OF 1,25-DIHYDROXYVITAMIN D-3 AND TAMOXIFEN ON THE GROWTH OF MCF-7 AND ZR-75-1 HUMAN BREAST-CANCER CELLS

In the present study we assessed the effect of combined treatment with 1,25-dihydroxyvitamin D-3 (1,25-OH)(2)D-3) and tamoxifen (TAM) on the growth of estrogen-responsive (MCF-7) and estrogen-dependent (ZR-75-1 ) human breast cancer cells. Both basal and 17 beta-estradiol (17 beta -E(2))-stimulated growth were studied. 1,25-(OH)(2)D-3(10(-10)-10(-7) M) time- and dose-dependently inhibited basal growth of MCF-7 cells, w ith growth arrest at 10(-7) M. Also, 17 beta-E(2)-stimulated growth of MCF-7 and ZR-75-1 cells was inhibited by 1,25-(OH)(2)D-3 in a time- a nd dose-dependent manner. TAM inhibited 17 beta-E(2)-stimulated growth of both cell lines and at high concentration (10(-6) M) it also inhib ited basal growth of MCF-7 cells. 10(-6) M TAM together with 1,25-(OH) (2)D-3 resulted in a further inhibition of basal (MCF-7 cells) as well as 17 beta-E(2)-stimulated proliferation (MCF-7 and ZR-75-1 cells) co mpared to the inhibition by these agents alone. TAM in combination wit h 10(-7) M 1,25(OH)(2)D-3 resulted in growth arrest of 17 beta-E(2)-st imulated growth of MCF-7 cells. The inhibition of basal and 17 beta-E( 2)-stimulated growth of MCF-7 cells was additive at early time points (4 days), but less than additive at later time points (8-10 days). It was demonstrated that with co-treatment of MCF-7 cells an equipotent i nhibition of basal growth could be reached with lower concentrations o f 1,25-(OH)(2)D-3, compared to treatment with 1,25-(OH)(2)D-3 alone. S tudies with low concentrations (< 10(-7) M) of TAM revealed a partial estrogenic effect, i.e. stimulation of MCF-7 proliferation in the abse nce of 17 beta-E(2). This effect, which may resemble TAM-induced tumor flare, was completely prevented by co-treatment with a low concentrat ion of 1,25-(OH)(2)D-3 (10(-9) M). Together, these results demonstrate the potent inhibition of breast cancer cell proliferation by 1,25-(OH )(2)D-3 combined with TAM and indicate a potential benefit of combinin g these agents for the treatment of breast cancer.