Summary
To elucidate the mechanisms involved in anti-oestrogen resistance, two human breast cancer cell lines MCF-7 and the ICI 182780-resistant cell line, MCF-7/182R-6, have been compared with regard to oestrogen receptor (ER) expression, ER function, ER regulation, growth requirements and differentially expressed gene products. MCF-7/182R-6 cells express a reduced level of ER protein. The ER protein is functional with respect to binding of oestradiol and the anti-oestrogens tamoxifen, 4-hydroxy-tamoxifen and ICI 182780, whereas expression and oestrogen induction of the progesterone receptor is lost in MCF-7/182R-6 cells. The ER protein and the ER mRNA are regulated similarly in the two cell lines when subjected to treatment with oestradiol or ICI 182780. Oestradiol down-regulates ER mRNA and ER protein expression. ICI 182780 has no initial effect on ER mRNA expression whereas the ER protein level decreases rapidly in cells treated with ICI 182780, indicating a severely decreased stability of the ER protein when bound to ICI 182780. In vitro growth experiments revealed that the ICI 182780-resistant cell line had evolved to an oestradiol-independent phenotype, able to grow with close to maximal growth rate both in the absence of oestradiol and in the presence of ICI 182780. Comparison of gene expression between the two cell lines revealed relatively few differences, indicating that a limited number of changes is involved in the development of anti-oestrogen resistance. Identification of the differentially expressed gene products are currently in progress.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Berkenstam, A., Glaumann, H., Martin, M., Gustafsson, JÅ & Norsted, G. (1989). Hormonal regulation of estrogen receptor messenger ribonucleic acid in T47Dco and MCF-7 breast cancer cells. Mol Endocrinol 3: 22–28.
Berthois, Y., Dong, X. F., Roux-Dossetto, M. & Martin, P. M. (1990). Expression of estrogen receptor and its messenger ribonucleic acid in the MCF-7 cell line: multiparametric analysis of its processing and regulation by estradiol. Mol Cell Endocrinol 74: 11–20.
Borrás, M., Hardy, L., Lempereue, F., El Khissiin, A. H., Legros, N., Gol-Winkler, R. & Leclercq, G. (1994). Estrogen-induced down-regulation of estrogen receptor. Effect of various modulators of protein synthesis and expression. J Steroid Biochem Mol Biol 48: 325–336.
Borrás, M., Laios, I., El Khissiin, A., Seo, H. S., Lempereur, F., Legros, N. & Leclercq, G. (1996). Estrogenic and antiestrogenic regulation of the half-life of covalently labeled estrogen receptor in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol 57: 203–213.
Briand, P. & Lykkesfeldt, A. E. (1984). Effect of estrogen and antiestrogen on the human breast cancer cell line MCF-7 adapted to grow at low serum concentration. Cancer Res 44: 1114–1119.
Clarke, R. & Brünner, N. (1996). Acquired estrogen independence and antiestrogen resistance in breast cancer. Estrogen receptor driven phenotypes? Trends Endocrinol Metab 7: 291–301.
Dauvois, S., Danielian, P. S., White, R. & Parker, M. G. (1992). Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover. Proc Natl Acad Sci USA 89: 4037–4041.
EORTC Breast Co-operative Group (1980). Revision of the standards for the assessment of hormone receptors in human breast cancer; report of the second EORTC workshop, held on 16–17 March, 1979, in the Netherlands Cancer Institute. Eur J Cancer 16: 1513–1515.
Gibson, M. K., Nemmers, L. A., Beckman, W. C., Davis, V. L., Curtis, S. W. & Korack, K. S. (1991). The mechanism of ICI 164,384 antiestrogenicity involves rapid loss of ER in uterine tissue. Endocrinology 129: 2000–2010.
Herman, M. E. & Katzenellenbogen, B. S. (1996). Response-specific antiestrogen resistance in a newly characterized MCF-7 human breast cancer cell line resulting from long-term exposure to trans-hydroxytamoxifen. J Steroid Biochem Mol Biol 59: 121–134.
Horwitz, K. B. & McGuire, W. L. (1978). Nuclear mechanisms of estrogen action. J Biol Chem 253: 8185–8191.
Howell, A., DeFriend, D. J., Robertson, J. F. R., Blamey, R. W. & Walton, P. (1995). Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer. Lancet 345: 29–30.
Hyder, S. M., Chiappetta, C., Murthy, L. & Stancel, G. M. (1997). Selective inhibition of estrogen-regulated gene expression in vivo by the pure antiestrogen ICI 182,780. Cancer Res 57: 2547–2549.
Johnston, S. R. D., Saccani-Jotti, G., Smith, I. E., Salter, J., Newby, J., Coppen, M., Ebbs, S. R. & Dowsett, M. (1995). Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. Cancer Res 55: 3331–3338.
Katzenellenbogen, B. S. (1991). Antiestrogen resistance: mechanisms by which breast cancer cells undermine the effectiveness of endocrine therapy. J Natl Cancer Inst 83: 1434–1444.
Laborda, J. (1991). 36B4 cDNA used as an estradiol-independent mRNA control is the cDNA for human acidic ribosomal phosphoprotein PO. Nucleic Acids Res 19: 3998
Larsen, S. S., Madsen, M. W., Jensen, B. L. & Lykkesfeldt, A. E. (1997). 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. Int J Cancer 72: 1129–1136.
Liang, P. & Pardee, A. B. (1992). Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science 257: 967–970.
Lykkesfeldt, A. E. (1996). Mechanisms of tamoxifen resistance in the treatment of advanced breast cancer. Acta Oncol 35: 9–14.
Lykkesfeldt, A. E., Madsen, M. W. & Briand, P. (1994). Altered expression of estrogen-regulated genes in a tamoxifen-resistant and ICI 164,384 and ICI 182,780 sensitive human breast cancer cell line, MCF-7/TAMR-1. Cancer Res 54: 1587–1595.
Lykkesfeldt, A. E., Larsen, S. S. & Briand, P. (1995). Human breast cancer cell lines resistant to pure anti-estrogens are sensitive to tamoxifen treatment. Int J Cancer 61: 529–534.
Madsen, M. W., Reiter, B. E. & Lykkesfeldt, A. E. (1995). Differential expression of estrogen receptor mRNA splice variants in the tamoxifen resistant human breast cancer cell line, MCF-7/TAMR/TAMR-1 compared to the parental MCF-7 cell line. Mol Cell Endocrinol 109: 197–207.
Masamura, S., Santner, S. J., Heitjan, D. F. & Santen, R. J. (1995). Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrinol Metab 80: 2918–2925.
Mouridsen, H., Palshof, T., Patterson, J. & Battersby, L. (1978). Tamoxifen in advanced breast cancer. Cancer Treat Rev 5: 131–141.
Osborne, C. K., Yochmowitz, M. G., Knight, W. A. & McGuire, W. L. (1980). The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 46: 2884–2888.
Osborne, C. K., Coronado-Heinsohn, E. B., Hilsenbeck, S. G., McCue, B. L., Wakeling, A. E., McClelland, R. A., Manning, D. L. & Nicholson, R. I. (1995). Comparison of the effects of pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 87: 746–750.
Pink, J. J. & Jordan, V. C. (1996). Models of estrogen receptor regulation by estrogens and antiestrogens in breast cancer cell lines. Cancer Res 56: 2321–2330.
Robertson, J. F. R. (1996). Oestrogen receptor: a stable phenotype in breast cancer. Br J Cancer 73: 5–12.
Saceda, M., Lippman, M. E., Chambon, P., Lindsey, R. L., Ponglikitmongkol, M., Puente, M. & Martin, M. B. (1988). Regulation of the estrogen receptor in MCF-7 cells by estradiol. Mol Endocrinol 2: 1157–1162.
Tora, L., White, J., Brou, C., Tasset, D., Webster, N., Scheer, E. & Chambon, P. (1989). The human estrogen receptor has two independent nonacidic transcriptional activation functions. Cell 59: 477–487.
van Agthoven, T., van Agthoven, T. L. A., Dekker, A., Foekens, J. A. & Dorssers, L. C. J. (1994). Induction of estrogen independence of ZR-75-1 human breast cancer cells by epigenetic alterations. Mol Endocrinol 8: 1474–1483.
Wakeling, A. E., Dukes, M. & Bowler, J. (1991). A potent specific pure antiestrogen with clinical potential. Cancer Res 51: 3867–3873.
Wakeling, A. E. (1993). Are breast tumours resistant to tamoxifen also resistant to pure antioestrogens?. J Steroid Biochem Mol Biol 47: 107–111.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Jensen, B., Skouv, J., Lundholt, B. et al. Differential regulation of specific genes in MCF-7 and the ICI 182780-resistant cell line MCF-7/182R-6. Br J Cancer 79, 386–392 (1999). https://doi.org/10.1038/sj.bjc.6690061
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690061
Keywords
This article is cited by
-
Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant
Breast Cancer Research and Treatment (2009)
-
A candidate molecular signature associated with tamoxifen failure in primary breast cancer
Breast Cancer Research (2008)
-
Characterization of a human breast cancer cell line, MCF-7/RU58R-1, resistant to the pure antiestrogen RU 58,668
Breast Cancer Research and Treatment (2005)