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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
Author(s) -
Larsen Søren S.,
Madsen Mogens W.,
Jensen Bettina L.,
Lykkesfeldt Anne E.
Publication year - 1997
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19970917)72:6<1129::aid-ijc31>3.0.co;2-x
Subject(s) - estrogen , estrogen receptor , endocrinology , medicine , cell culture , biology , estrogen receptor alpha , mcf 7 , fulvestrant , estrogen receptor beta , gene expression , progesterone receptor , steroid sulfatase , basal (medicine) , cancer cell , hormone , cancer , gene , breast cancer , human breast , steroid , genetics , insulin
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 breast‐cancer 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 anti‐estrogens 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, α 1 ‐anti‐trypsin 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‐182,780‐resistant phenotype. Int. J. Cancer 72:1129–1136, 1997. © 1997 Wiley‐Liss, Inc.