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Tenovus Centre for Cancer Research (J.M.K., I.R.H., H.E.J., T.M., J.M.W.G., M.E.H., D.B., R.I.N.), Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3XF, United Kingdom; and AstraZeneca (A.E.W.), Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
Address all correspondence and requests for reprints to: Iain R. Hutcheson, Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, United Kingdom. E-mail: hutchesonir{at}cf.ac.uk.
The development of acquired resistance to antihormonal agents in breast cancer is a major therapeutic problem. We have developed a tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell line to investigate the mechanisms behind this condition. Both epidermal growth factor receptor (EGFR) and c-erbB2 mRNA and protein expression were increased in TAM-R compared with wild-type MCF-7 cells, whereas comparable levels of c-erbB3 mRNA and protein were expressed in both cell lines. Under basal conditions, phosphorylated EGFR/c-erbB2, EGFR/c-erbB3 but not c-erbB2/c-erbB3 receptor heterodimers were detected in TAM-R cells in association with increased levels of phosphorylated extracellular-signal regulated kinase 1/2 (ERK1/2). Both cell lines were capable of generating a range of EGFR-specific ligands and increased expression of transforming growth factor 
was observed in TAM-R cells. Treatment of TAM-R cells with ZD1839 (Iressa) or trastuzumab (Herceptin) blocked c-erbB receptor heterodimer formation and phosphorylation, reduced ERK1/2 activity, and strongly inhibited cell growth. The MAPK kinase inhibitor PD098059 specifically reduced phosphorylated ERK1/2 levels and inhibited TAM-R growth. All three agents abolished ERK1/2 activity in wild-type cells but caused only small reductions in cell proliferation. These results demonstrate that TAM-R MCF-7 cell growth is mediated by the autocrine release and action of an EGFR-specific ligand inducing preferential EGFR/c-erbB2 dimerization and downstream activation of the ERK pathway.
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M. C. Gutierrez, S. Detre, S. Johnston, S. K. Mohsin, J. Shou, D. C. Allred, R. Schiff, C. K. Osborne, and M. Dowsett Molecular Changes in Tamoxifen-Resistant Breast Cancer: Relationship Between Estrogen Receptor, HER-2, and p38 Mitogen-Activated Protein Kinase J. Clin. Oncol., April 10, 2005; 23(11): 2469 - 2476. [Abstract] [Full Text] [PDF]
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S. R. Johnston Combinations of Endocrine and Biological Agents: Present Status of Therapeutic and Presurgical Investigations Clin. Cancer Res., January 15, 2005; 11(2): 889s - 899s. [Abstract] [Full Text] [PDF]
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I. Chu, K. Blackwell, S. Chen, and J. Slingerland The Dual ErbB1/ErbB2 Inhibitor, Lapatinib (GW572016), Cooperates with Tamoxifen to Inhibit Both Cell Proliferation- and Estrogen-Dependent Gene Expression in Antiestrogen-Resistant Breast Cancer Cancer Res., January 1, 2005; 65(1): 18 - 25. [Abstract] [Full Text] [PDF]
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R I Nicholson, C Staka, F Boyns, I R Hutcheson, and J M W Gee Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy Endocr. Relat. Cancer, December 1, 2004; 11(4): 623 - 641. [Abstract] [Full Text] [PDF]
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A. Ring and M. Dowsett Mechanisms of tamoxifen resistance Endocr. Relat. Cancer, December 1, 2004; 11(4): 643 - 658. [Abstract] [Full Text] [PDF]
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H E Jones, L Goddard, J M W Gee, S Hiscox, M Rubini, D Barrow, J M Knowlden, S Williams, A E Wakeling, and R I Nicholson Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells Endocr. Relat. Cancer, December 1, 2004; 11(4): 793 - 814. [Abstract] [Full Text] [PDF]
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M. B. Buck, K. Pfizenmaier, and C. Knabbe Antiestrogens Induce Growth Inhibition by Sequential Activation of p38 Mitogen-Activated Protein Kinase and Transforming Growth Factor-{beta} Pathways in Human Breast Cancer Cells Mol. Endocrinol., July 1, 2004; 18(7): 1643 - 1657. [Abstract] [Full Text] [PDF]
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M. Sumitomo, T. Asano, J. Asakuma, T. Asano, A. Horiguchi, and M. Hayakawa ZD1839 Modulates Paclitaxel Response in Renal Cancer by Blocking Paclitaxel-Induced Activation of the Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase Pathway Clin. Cancer Res., January 15, 2004; 10(2): 794 - 801. [Abstract] [Full Text] [PDF]
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R. I. Nicholson, I. R. Hutcheson, J. M. Knowlden, H. E. Jones, M. E. Harper, N. Jordan, S. E. Hiscox, D. Barrow, and J. M. W. Gee Nonendocrine Pathways and Endocrine Resistance: Observations with Antiestrogens and Signal Transduction Inhibitors in Combination Clin. Cancer Res., January 1, 2004; 10(1): 346S - 354S. [Abstract] [Full Text] [PDF]
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 G. E. Konecny, C. A. Wilson, and D. J. Slamon Is There a Role for Epidermal Growth Factor Receptor Inhibitors in Breast Cancer Prevention? J Natl Cancer Inst, December 17, 2003; 95(24): 1813 - 1815. [Full Text] [PDF]
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J. M. W. Gee, M. E. Harper, I. R. Hutcheson, T. A. Madden, D. Barrow, J. M. Knowlden, R. A. McClelland, N. Jordan, A. E. Wakeling, and R. I. Nicholson The Antiepidermal Growth Factor Receptor Agent Gefitinib (ZD1839/Iressa) Improves Antihormone Response and Prevents Development of Resistance in Breast Cancer in Vitro Endocrinology, November 1, 2003; 144(11): 5105 - 5117. [Abstract] [Full Text] [PDF]
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F. Spyratos, C. Bouchet, M. Ferrero-Pous, M. Tubiana-Hulin, and K. Hacene Re: Quantitative Association Between HER-2/neu and Steroid Hormone Receptors in Hormone Receptor-Positive Primary Breast Cancer J Natl Cancer Inst, September 17, 2003; 95(18): 1417 - 1418. [Full Text] [PDF]
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