DIFFERENTIAL SENSITIVITY OF HUMAN-BREAST CANCER CELL-LINES TO THE GROWTH-INHIBITORY EFFECTS OF TAMOXIFEN

Abstract

In 8 estrogen receptor (ER)-positive breast cancer cell lines (including 3 sublines of MCF-7) and 5 ER-negative breast lines, the action of the nonsteroidal antiestrogen, tamoxifen, was studied, and the concentrations of ER and antiestrogen binding site were measured. The concentration of antiestrogen binding site was significantly [P < 0.005] greater in ER-positive cells [236,600 .+-. 29,9000 (SE) sites/cell] than in ER-negative cell lines [66,600 .+-. 16,800 sites/cell]. In ER-positive cell lines, a cell cycle phase-specific growth inhibitory effect, 20% inhibitory dose < 0.1 to 1.0 .mu.M, was seen which was shown for some representative cell lines to be estrogen reversible. Within this group of cell lines, the degree of tamoxifen-induced inhibition of growth correlated with control population doubling time, but not ER or antieistrogen binding site concentration. The changes in cell cycle kinetic parameters characteristic of all ER-positive lines were a decrease in percentage of S-phase cells and a corresponding increase in percentage of G0-G1 cells. In all cell lines 5-12.5 .mu.M tamoxifen caused cytotoxicity, and this was estrogen-irreversible in 3 representative cell lines; moreover, estradiol synergistically enhanced the cytotoxic effects of tamoxifen under some experimental conditions. The cell cycle effects of tamoxifen in 3 ER-negative cell lines (Hs0578T, MDA-MB-231, MDA-MB-330) were decreased proportions of G0-G1 cells with an increase in percentages of S and G2+M cells. These results implied that the mechanism of tamoxifen cytotoxicity may differ in ER-positive and ER-negative breast cancer cells. Although the ER-negative BT-20 lines was much less sensitive to tamoxifen than were the ER-positive cells, growth inhibition and cytotoxicity in this line were associated with a slight decrease in percentage of S-phase cells. These results confirm that ER-positive breast cancer cells are most sensitive (4- to > 75-fold) than ER-negative breast cells to the growth-inhibitory effects of tamoxifen and demonstrate that, in all ER-positive cells, growth inhibition and cytotoxicity are accompanied by characteristic changes in cell cycle kinetic parameters. In contrast, different mechanisms may be involved in the effects of tamoxifen on different ER-negative cell lines.