Resistance of human breast-cancer cells to the pure steroidal anti-estrogen ICI 182,780 is not associated with a general loss of estrogen-receptor expression or lack of estrogen responsiveness
✍ Scribed by Søren S. Larsen; Mogens W. Madsen; Bettina L. Jensen; Anne E. Lykkesfeldt
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- French
- Weight
- 145 KB
- Volume
- 72
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
To elucidate the mechanisms responsible for the development of anti-estrogen 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 human breastcancer MCF-7 cell line by long-term treatment with 10 ؊7 M ICI 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 sub-lines. In the MCF-7 cell line we find that ER expression is regulated by estrogen and antiestrogens at the transcriptional and post-transcriptional 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 expression level. The resistant sub-lines also deviate from parent characteristics by the complete lack of expression of progesterone receptor even when grown in the presence of estradiol. All 3 resistant sub-lines have a lower basal expression of cathepsin-D mRNA comparable with the lower ER expression, but, in contrast, they have higher basal expression 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 receptors in the resistant sub-lines have also maintained wild-type characteristics with respect to estrogen and anti-estrogen regulation of the estrogen-regulated proteins procathepsin D, ␣ 1 -antitrypsin and a 42-kDa protein. The resistant cells require estrogen for growth in athymic nude mice. Our results clearly demonstrate that the ER in the resistant sub-lines have a normal function for most parameters investigated, supporting our earlier observation that only wild-type ER protein is expressed in these cells. The few observed differences in ER function between the parent MCF-7 cell line and the resistant sub-lines are not likely to be responsible for the ICI-182,780resistant phenotype. Int.