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Differential Sensitivity of Human Breast Cancer Cell Lines to the Growth-inhibitory Effects of Tamoxifen

Ludwig Institute for Cancer Research (Sydney Branch), Blackburn Building, University of Sydney, Sydney, New South Wales 2006, Australia

In eight estrogen receptor (ER)-positive breast cancer cell lines (including three sublines of MCF-7) and five 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 ± 29,900 (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 µM, 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 antiestrogen 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 to 12.5 µM tamoxifen caused cytotoxicity, and this was shown to be 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 three ER-negative cell lines (Hs0578T, MDA-MB-231, MDA-MB-330) were decreased proportions of G₀-G₁ cells with an increase in percent-ages 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. However, although the ER-negative BT-20 line 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 more 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.

¹ To whom requests for reprints should be addressed.

Received 11/ 2/83. Revised 10/ 1/84. Revised 12/ 5/84. Accepted 12/27/84.

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