MODULATION OF CELL-CYCLE CONTROL BY VITAMIN-D-3 AND ITS ANALOG, EB1089, IN HUMAN BREAST-CANCER CELLS

Examination of a panel of ER positive breast cancer cell lines showed that they were differentially growth inhibited by vitamin D-3 and its analogue EB1089. EB1089 treatment of the breast cancer cell lines MCF- 7 E, BT20, T47D, and ZR75 demonstrated a correlation between a reducti on in Cdk2 kinase activity towards phosphorylation of histone H1 and a decrease in DNA synthesis, while no modulation of Cdk2 activity was o bserved in the vitamin D-3 and EB1089 resistant cell line MCF-7 L. Thi s was accompanied by a time dependent decrease in the percentage of S phase cells in the responsive lines. Characterization of the expressio n levels of Cdk2 and its related cell cycle proteins in MCF-7 E cells showed that after EB1089 treatment, there was a concentration and time dependent up-regulation of p21 as well as a decrease in cyclin A prot eins. Paradoxically, cyclin E levels were increased as a function of t reatment. Analysis of cyclin-Cdk2-Cdki complex formation showed that i n EB1089 treated MCF-7 E cells, Cdk2, cyclin A and cyclin E immunoprec ipitates contained an increased abundance of p21. In contrast to MCF-7 E cells, increases in both p21 and p27 as well as their complex forma tion with Cdk2 were observed in BT20 and ZR75 cells. These findings in dicate that up-regulation of p21 as well as p27 in some cell types mag account for the inactivation of Cdk2 activity and a G(1) block of the cell cycle following EB1089 treatment.