RESISTANCE OF HUMAN BREAST-CANCER CELLS TO THE PURE STEROIDAL ANTIESTROGEN ICI-182,780 IS NOT ASSOCIATED WITH A GENERAL LOSS OF ESTROGEN-RECEPTOR EXPRESSION OR LACK OF ESTROGEN RESPONSIVENESS

To elucidate the mechanisms responsible for the development of anti-es trogen resistance, we have cloned and established 3 stable ICI-182,780 -resistant sub lines, MCF-7/182(R)-1, MCF-7/182(R)-6 and MCF-7/182(R)- 7 from the estrogen-receptor(ER)-positive and estrogen-responsive huma n breast-cancer MCF-7 cell line by long-term treatment with 10(-7) M I CI 182,780. The ICI-182,780 resistant MCF-7 sub-lines express ER, but compared with MCF-7 cells the level is significantly lower in all 3 su b-lines. In the MCF-7 cell line we find that ER expression is regulate d by estrogen and antiestrogens at the transcriptional and post-transc riptional level. This is in contrast to the ICI-182,780-resistant sub- lines, in which we find very little hormonal effects on the ER mRNA ex pression level. The resistant sub-lines also deviate from parent chara cteristics by the complete lack of expression of progesterone receptor even when grown in the presence of estradiol. All 3 resistant sub-lin es have a lower basal expression of cathepsin-D mRNA comparable with t he lower ER expression, but, in contrast, they have higher basal expre ssion of the pS2 mRNA than the parent MCF-7 cell line. Although there are different basal expression levels of the pS2 and cathepsin-D genes , the resistant sub-lines behave like the parent MCF-7 cell line with respect to the hormonal regulation of both genes. The estrogen recepto rs in the resistant sub-lines have also maintained wild-type character istics with respect to estrogen and anti-estrogen regulation of the es trogen-regulated proteins procathepsin D, alpha(1)-anti-trypsin and a 42-kDa protein. The resistant cells require estrogen for growth in ath ymic nude mice. Our results clearly demonstrate that the ER in the res istant sub-lines have a normal function for most parameters investigat ed, supporting our earlier observation that only wild type ER protein is expressed in these cells. The few observed differences in ER functi on between the parent MCF-7 cell line and the resistant sub-lines are not likely to be responsible for the ICI-182,780-resistant phenotype. (C) 1997 Wiley-Liss, Inc.