This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chu, I. Articles by Slingerland, J. Search for Related Content PubMed PubMed Citation Articles by Chu, I. Articles by Slingerland, J.

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

¹ The Braman Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center and ² Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, Florida; ³ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and ⁴ Division of Medical Oncology, Department of Medicine, Duke University Comprehensive Cancer Center, Durham, North Carolina

Request for reprints: J. Slingerland, UM Sylvester Comprehensive Cancer Center, 1475 N.W. 12^th Ave., (D8-4), Miami FL 33136. Phone: 305-243-7265; E-mail: jslingerland{at}med.miami.edu or K. Blackwell, Box 3893DUMC, Durham NC 27710. Phone: 919-681-2901; E-mail: black034{at}mc.duke.edu.

Effective treatment of estrogen receptor (ER)-positive breast cancers with tamoxifen is often curtailed by the development of drug resistance. Antiestrogen-resistant breast cancers often show increased expression of the epidermal growth factor receptor family members, ErbB1 and ErbB2. Tamoxifen activates the cyclin-dependent kinase inhibitor, p27 to mediate G₁ arrest. ErbB2 or ErbB1 overexpression can abrogate tamoxifen sensitivity in breast cancer lines through both reduction in p27 levels and inhibition of its function. Here we show that the dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), can restore tamoxifen sensitivity in ER-positive, tamoxifen-resistant breast cancer models. Treatment of MCF-7^pr, T-47D, and ZR-75 cells with lapatinib or tamoxifen alone caused an incomplete cell cycle arrest. Treatment with both drugs led to a more rapid and profound cell cycle arrest in all three lines. Mitogen-activated protein kinase and protein kinase B were inhibited by lapatinib. The two drugs together caused a greater reduction of cyclin D1 and a greater p27 increase and cyclin E-cdk2 inhibition than observed with either drug alone. In addition to inhibiting mitogenic signaling and cell cycle progression, lapatinib inhibited estrogen-stimulated ER transcriptional activity and cooperated with tamoxifen to further reduce ER-dependent transcription. Lapatinib in combination with tamoxifen effectively inhibited the growth of tamoxifen-resistant ErbB2 overexpressing MCF-7 mammary tumor xenografts. These data provide strong preclinical data to support clinical trials of ErbB1/ErbB2 inhibitors in combination with tamoxifen in the treatment of human breast cancer.

Key Words: Cell cycle • ErbB1 • ErbB2 • signal transduction • MAPK • PI3K • breast cancer • p27

This article has been cited by other articles:

				G. Arpino, L. Wiechmann, C. K. Osborne, and R. Schiff Crosstalk between the Estrogen Receptor and the HER Tyrosine Kinase Receptor Family: Molecular Mechanism and Clinical Implications for Endocrine Therapy Resistance Endocr. Rev., April 1, 2008; 29(2): 217 - 233. [Abstract] [Full Text] [PDF]

				S. Massarweh, C. K. Osborne, C. J. Creighton, L. Qin, A. Tsimelzon, S. Huang, H. Weiss, M. Rimawi, and R. Schiff Tamoxifen Resistance in Breast Tumors Is Driven by Growth Factor Receptor Signaling with Repression of Classic Estrogen Receptor Genomic Function Cancer Res., February 1, 2008; 68(3): 826 - 833. [Abstract] [Full Text] [PDF]

				L.-A. Martin, J. E. Head, S. Pancholi, J. Salter, E. Quinn, S. Detre, S. Kaye, A. Howes, M. Dowsett, and S. R.D. Johnston The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo Mol. Cancer Ther., September 1, 2007; 6(9): 2458 - 2467. [Abstract] [Full Text] [PDF]

				A. K. Chen, M. A. Behlke, and A. Tsourkas Avoiding false-positive signals with nuclease-vulnerable molecular beacons in single living cells Nucleic Acids Res., August 15, 2007; (2007) gkm593v1. [Abstract] [Full Text] [PDF]

				B. Moy and P. E. Goss Lapatinib-Associated Toxicity and Practical Management Recommendations Oncologist, July 1, 2007; 12(7): 756 - 765. [Abstract] [Full Text] [PDF]

				N. V. Dimitrov, P. Colucci, and S. Nagpal Some Aspects of the Endocrine Profile and Management of Hormone-Dependent Male Breast Cancer Oncologist, July 1, 2007; 12(7): 798 - 807. [Abstract] [Full Text] [PDF]

				P. S. Hegde, D. Rusnak, M. Bertiaux, K. Alligood, J. Strum, R. Gagnon, and T. M. Gilmer Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles Mol. Cancer Ther., May 1, 2007; 6(5): 1629 - 1640. [Abstract] [Full Text] [PDF]

				R. Nahta, L. X.H. Yuan, Y. Du, and F. J. Esteva Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling Mol. Cancer Ther., February 1, 2007; 6(2): 667 - 674. [Abstract] [Full Text] [PDF]

				M. Failly, S. Korur, V. Egler, J.-L. Boulay, M. M. Lino, R. Imber, and A. Merlo Combination of sublethal concentrations of epidermal growth factor receptor inhibitor and microtubule stabilizer induces apoptosis of glioblastoma cells Mol. Cancer Ther., February 1, 2007; 6(2): 773 - 781. [Abstract] [Full Text] [PDF]

				C. Yang, S. Trent, V. Ionescu-Tiba, L. Lan, T. Shioda, D. Sgroi, and E. V. Schmidt Identification of Cyclin D1- and Estrogen-Regulated Genes Contributing to Breast Carcinogenesis and Progression Cancer Res., December 15, 2006; 66(24): 11649 - 11658. [Abstract] [Full Text] [PDF]

				P. L. Porter, W. E. Barlow, I-T. Yeh, M. G. Lin, X. P. Yuan, E. Donato, G. W. Sledge, C. L. Shapiro, J. N. Ingle, C. M. Haskell, et al. p27Kip1 and Cyclin E Expression and Breast Cancer Survival After Treatment With Adjuvant Chemotherapy J Natl Cancer Inst, December 6, 2006; 98(23): 1723 - 1731. [Abstract] [Full Text] [PDF]

				S. Massarweh and R. Schiff Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S15 - S24. [Abstract] [Full Text] [PDF]

				B. Moy and P. E. Goss Lapatinib: Current Status and Future Directions in Breast Cancer Oncologist, November 1, 2006; 11(10): 1047 - 1057. [Abstract] [Full Text] [PDF]

				A. Tzankov, A. Gschwendtner, F. Augustin, M. Fiegl, E. C. Obermann, S. Dirnhofer, and P. Went Diffuse large B-cell lymphoma with overexpression of cyclin e substantiates poor standard treatment response and inferior outcome. Clin. Cancer Res., April 1, 2006; 12(7): 2125 - 2132. [Abstract] [Full Text] [PDF]

				P. Tang, X. Wang, L. Schiffhauer, J. Wang, P. Bourne, Q. Yang, A. Quinn, and S. Hajdu Expression Patterns of ER-{alpha}, PR, HER-2/neu, and EGFR in Different Cell Origin Subtypes of High Grade and Non-High Grade Ductal Carcinoma In Situ. Ann. Clin. Lab. Sci., March 1, 2006; 36(2): 137 - 143. [Abstract] [Full Text] [PDF]

				J. M. du Manoir, G. Francia, S. Man, M. Mossoba, J. A. Medin, A. Viloria-Petit, D. J. Hicklin, U. Emmenegger, and R. S. Kerbel Strategies for Delaying or Treating In vivo Acquired Resistance to Trastuzumab in Human Breast Cancer Xenografts Clin. Cancer Res., February 1, 2006; 12(3): 904 - 916. [Abstract] [Full Text] [PDF]

				S. R.D. Johnston Clinical Efforts to Combine Endocrine Agents with Targeted Therapies against Epidermal Growth Factor Receptor/Human Epidermal Growth Factor Receptor 2 and Mammalian Target of Rapamycin in Breast Cancer Clin. Cancer Res., February 1, 2006; 12(3): 1061s - 1068s. [Abstract] [Full Text] [PDF]

				M. H Nelson and C. R Dolder Lapatinib: A Novel Dual Tyrosine Kinase Inhibitor with Activity in Solid Tumors Ann. Pharmacother., February 1, 2006; 40(2): 261 - 269. [Abstract] [Full Text] [PDF]

				Y. Zhou, S. Li, Y. P. Hu, J. Wang, J. Hauser, A. N. Conway, M. A. Vinci, L. Humphrey, E. Zborowska, J. K.V. Willson, et al. Blockade of EGFR and ErbB2 by the Novel Dual EGFR and ErbB2 Tyrosine Kinase Inhibitor GW572016 Sensitizes Human Colon Carcinoma GEO Cells to Apoptosis Cancer Res., January 1, 2006; 66(1): 404 - 411. [Abstract] [Full Text] [PDF]

				C. V. Lund, M. Popkov, L. Magnenat, and C. F. Barbas III Zinc Finger Transcription Factors Designed for Bispecific Coregulation of ErbB2 and ErbB3 Receptors: Insights into ErbB Receptor Biology Mol. Cell. Biol., October 15, 2005; 25(20): 9082 - 9091. [Abstract] [Full Text] [PDF]

				T. Takahashi, M. Ohmichi, J. Kawagoe, C. Ohshima, M. Doshida, T. Ohta, M. Saitoh, A. Mori-Abe, B. Du, H. Igarashi, et al. Growth Factors Change Nuclear Distribution of Estrogen Receptor-{alpha} via Mitogen-Activated Protein Kinase or Phosphatidylinositol 3-Kinase Cascade in a Human Breast Cancer Cell Line Endocrinology, September 1, 2005; 146(9): 4082 - 4089. [Abstract] [Full Text] [PDF]

				A. J Butt, C. M McNeil, E. A Musgrove, and R. L Sutherland Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S47 - S59. [Abstract] [Full Text] [PDF]

				S R D Johnston Clinical trials of intracellular signal transductions inhibitors for breast cancer -- a strategy to overcome endocrine resistance Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S145 - S157. [Abstract] [Full Text] [PDF]

				A E Wakeling Inhibitors of growth factor signalling Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S183 - S187. [Abstract] [Full Text] [PDF]