Acquired resistance to antiestrogens is a major problem in the clinical management of initially endocrine responsive metastatic breast cancer. We have shown previously that estrogen-independent and -responsive MCF7/LCC1 human breast cancer cells selected for resistance to the triphenylethylene tamoxifen produce a variant (MCF7/LCC2) that retains sensitivity to the steroidal antiestrogen ICI 182,780 (N. Brünner et al., Cancer Res., 53: 3229–3232, 1993). We have now applied stepwise selections in vitro from 10 pm to 1 µm ICI 182,780 against MCF7/LCC1 and obtained a stable ICI 182,780-resistant variant designated MCF7/LCC9. In contrast to 4-hydroxytamoxifen-selected MCF7/LCC2 cells, MCF7/LCC9 cells exhibit full cross-resistance to tamoxifen, despite never having been exposed to this drug. Significantly, tamoxifen cross-resistance arose early in the selection, appearing following selection against only 0.1 nm ICI 182,780. Although limited resistance to ICI 182,780 also was observed, full ICI 182,780 resistance was not detected until the selective pressure increased to 100 nm ICI 182,780. Cross-resistance to tamoxifen persisted throughout these additional selections. Despite their antiestrogen cross-resistance, MCF7/LCC9 cells retain a level of estrogen receptor expression comparable to that of their parental MCF7/LCC1 cells. Whereas MCF7/LCC1 cells retain an estrogen-inducible expression of progesterone receptors, MCF7/LCC9 cells exhibit an up-regulated expression of both progesterone receptor mRNA and protein that is no longer estrogen responsive. Estrogen-independent and -responsive components of the MCF7/LCC9 phenotype are apparent in vivo. These cells form slowly growing tumors in ovariectomized athymic nude mice but respond mitogenically upon estrogenic supplementation. The in vivo growth of MCF7/LCC9 tumors is not affected by treatment with ICI 182,780. Although there is some evidence of tamoxifen stimulation of tumor growth, this did not reach statistical significance. If this pattern of cross-resistance occurs in some breast cancer patients, administering triphenylethylene antiestrogens as a first-line therapy with a cross-over to steroidal compounds upon recurrence may be advantageous.
This study was supported by United States Public Health Service Grants R01-CA58022 and P30-CA51008 from the National Cancer Institute (to R. C.) and Grant 95-010 from the Danish Cancer Society (to N. B.).