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Inhibition of HER2/neu (erbB-2) and Mitogen-activated Protein Kinases Enhances Tamoxifen Action against HER2-overexpressing, Tamoxifen-resistant Breast Cancer Cells¹

Departments of Medicine [H. K., A. E. G. L., J. T. F., C. L. A.], Cell Biology [C. L. A.], and Pathology [J. F. S., J. T. F.], Vanderbilt University School of Medicine, Department of Veteran Affairs Medical Center [C. L. A.] and Vanderbilt-Ingram Cancer Center [J. F. S., C. L. A.], Nashville, Tennessee 37232, and Genentech, Inc. South San Francisco, California 94080 [P. I. P., M. X. S.]

HER2/neu (erbB-2) overexpression has been causally associated with tamoxifen resistance in human breast cancer cells. Forced expression of HER2 in MCF-7 breast cancer cells resulted in mitogen-activated protein kinase (MAPK) hyperactivity and tamoxifen resistance. Inhibition of HER2 and MAPKs with AG1478 and U0126, respectively, as well as dominant-negative MEK-1/2 constructs restored the inhibitory effect of tamoxifen on estrogen receptor (ER)-mediated transcription and cell proliferation. Both AG1478 and U0126 also restored the tamoxifen-mediated association of ER with nuclear receptor corepressor (N-CoR) in the antiestrogen-resistant MCF-7 cells. Treatment with a combination of tamoxifen and a HER2 kinase inhibitor reduced tumor MAPK activity and markedly prevented growth of HER2-overexpressing MCF-7 xenografts in athymic mice. Thus, blockade of HER2 and MAPK signaling may enhance tamoxifen action and abrogate antiestrogen resistance in human breast cancer.

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				H. Kurokawa and C. L. Arteaga ErbB (HER) Receptors Can Abrogate Antiestrogen Action in Human Breast Cancer by Multiple Signaling Mechanisms Clin. Cancer Res., January 1, 2003; 9(1): 511S - 515S. [Abstract] [Full Text] [PDF]

				S. R. D. Johnston, J. Head, S. Pancholi, S. Detre, L.-A. Martin, I. E. Smith, and M. Dowsett Integration of Signal Transduction Inhibitors with Endocrine Therapy: An Approach to Overcoming Hormone Resistance in Breast Cancer Clin. Cancer Res., January 1, 2003; 9(1): 524S - 532S. [Abstract] [Full Text] [PDF]

				K. Wu, C. Wang, M. D'Amico, R. J. Lee, C. Albanese, R. G. Pestell, and S. Mani Flavopiridol and Trastuzumab Synergistically Inhibit Proliferation of Breast Cancer Cells: Association with Selective Cooperative Inhibition of Cyclin D1-dependent Kinase and Akt Signaling Pathways Mol. Cancer Ther., July 1, 2002; 1(9): 695 - 706. [Abstract] [Full Text] [PDF]

				A. Bowman, H. Gabra, S. P. Langdon, A. Lessells, M. Stewart, A. Young, and J. F. Smyth CA125 Response Is Associated with Estrogen Receptor Expression in a Phase II Trial of Letrozole in Ovarian Cancer: Identification of an Endocrine-sensitive Subgroup Clin. Cancer Res., July 1, 2002; 8(7): 2233 - 2239. [Abstract] [Full Text] [PDF]

				V. G. Keshamouni, R. R. Mattingly, and K. B. Reddy Mechanism of 17-beta -Estradiol-induced Erk1/2 Activation in Breast Cancer Cells. A ROLE FOR HER2 AND PKC-delta J. Biol. Chem., June 14, 2002; 277(25): 22558 - 22565. [Abstract] [Full Text] [PDF]

				A. Adeyinka, Y. Nui, T. Cherlet, L. Snell, P. H. Watson, and L. C. Murphy Activated Mitogen-activated Protein Kinase Expression during Human Breast Tumorigenesis and Breast Cancer Progression Clin. Cancer Res., June 1, 2002; 8(6): 1747 - 1753. [Abstract] [Full Text] [PDF]

				G. K. Scott, C. Marden, F. Xu, L. Kirk, and C. C. Benz Transcriptional Repression of ErbB2 by Histone Deacetylase Inhibitors Detected by a Genomically Integrated ErbB2 Promoter-reporting Cell Screen Mol. Cancer Ther., April 1, 2002; 1(6): 385 - 392. [Abstract] [Full Text] [PDF]

				E. R. Simpson and M. Dowsett Aromatase and Its Inhibitors: Significance for Breast Cancer Therapy Recent Prog. Horm. Res., January 1, 2002; 57(1): 317 - 338. [Abstract] [Full Text] [PDF]

				M. Dowsett, C. Harper-Wynne, I. Boeddinghaus, J. Salter, M. Hills, M. Dixon, S. Ebbs, G. Gui, N. Sacks, and I. Smith HER-2 Amplification Impedes the Antiproliferative Effects of Hormone Therapy in Estrogen Receptor-positive Primary Breast Cancer Cancer Res., December 1, 2001; 61(23): 8452 - 8458. [Abstract] [Full Text] [PDF]

				I. Hoffmann, E. Eugene, X. Nassif, P.-O. Couraud, and S. Bourdoulous Activation of ErbB2 receptor tyrosine kinase supports invasion of endothelial cells by Neisseria meningitidis J. Cell Biol., October 1, 2001; 155(1): 133 - 144. [Abstract] [Full Text] [PDF]

				A. E. G. Lenferink, D. Busse, W. M. Flanagan, F. M. Yakes, and C. L. Arteaga ErbB2/neu Kinase Modulates Cellular p27Kip1 and Cyclin D1 through Multiple Signaling Pathways Cancer Res., September 1, 2001; 61(17): 6583 - 6591. [Abstract] [Full Text] [PDF]

				R. A. McClelland, D. Barrow, T.-A. Madden, C. M. Dutkowski, J. Pamment, J. M. Knowlden, J. M. W. Gee, and R. I. Nicholson Enhanced Epidermal Growth Factor Receptor Signaling in MCF7 Breast Cancer Cells after Long-Term Culture in the Presence of the Pure Antiestrogen ICI 182,780 (Faslodex) Endocrinology, July 1, 2001; 142(7): 2776 - 2788. [Abstract] [Full Text] [PDF]

				R. Bagatell, O. Khan, G. Paine-Murrieta, C. W. Taylor, S. Akinaga, and L. Whitesell Destabilization of Steroid Receptors by Heat Shock Protein 90-binding Drugs: A Ligand-independent Approach to Hormonal Therapy of Breast Cancer Clin. Cancer Res., July 1, 2001; 7(7): 2076 - 2084. [Abstract] [Full Text] [PDF]

				J.-i. Okano and A. K. Rustgi Paclitaxel Induces Prolonged Activation of the Ras/MEK/ERK Pathway Independently of Activating the Programmed Cell Death Machinery J. Biol. Chem., May 25, 2001; 276(22): 19555 - 19564. [Abstract] [Full Text] [PDF]

				J. C. H. Donovan, A. Milic, and J. M. Slingerland Constitutive MEK/MAPK Activation Leads to p27Kip1 Deregulation and Antiestrogen Resistance in Human Breast Cancer Cells J. Biol. Chem., October 26, 2001; 276(44): 40888 - 40895. [Abstract] [Full Text] [PDF]