| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Endocrinology |
1 Department of Internal Medicine and Markey Cancer Center, University of Kentucky, Lexington, Kentucky; 2 Breast Center and Departments of 3 Medicine and 4 Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; and 5 Cancer & Infection Bioscience, AstraZeneca, Macclesfield, United Kingdom
Requests for reprints: Rachel Schiff, Breast Center, Baylor College of Medicine, Room N1230.02, One Baylor Plaza, BCM 600, Houston, TX 77030. Phone: 713-798-1676; Fax: 713-798-1659; E-mail: rschiff{at}breastcenter.tmc.edu.
HER-2/neu in breast cancer is associated with tamoxifen resistance, but little data exist on its interaction with estrogen deprivation or fulvestrant. Here, we used an in vivo xenograft model of estrogen receptor (ER)-positive breast cancer with HER-2/neu overexpression (MCF7/HER-2/neu-18) to investigate mechanisms of growth inhibition and treatment resistance. MCF7/HER-2/neu-18 tumors were growth inhibited by estrogen deprivation and with fulvestrant, but resistance developed in 2 to 3 months. Inhibited tumors had reductions in ER, insulin-like growth factor-I receptor (IGF-IR), phosphorylated HER-2/neu (p-HER-2/neu), and phosphorylated p42/44 mitogen-activated protein kinase (p-MAPK). p27 was increased especially in tumors sensitive to estrogen deprivation. Tumors with acquired resistance to these therapies had complete loss of ER, increased p-HER-2/neu, increased p-MAPK, and reduced p27. In contrast, IGF-IR and phosphorylated AKT (p-AKT) levels were markedly reduced in these resistant tumors. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib, which can block EGFR/HER-2/neu signaling, significantly delayed the emergence of resistance to both estrogen deprivation and fulvestrant. Levels of p-MAPK and p-AKT decreased with gefitinib, whereas high ER levels were restored. Eventually, however, tumors progressed in mice treated with gefitinib combined with estrogen deprivation or fulvestrant accompanied again by loss of ER and IGF-IR, increased p-HER-2/neu, high p-MAPK, and now increased p-AKT. Thus, estrogen deprivation and fulvestrant can effectively inhibit HER-2/neu-overexpressing tumors but resistance develops quickly. EGFR/HER-2/neu inhibitors can delay resistance, but reactivation of HER-2/neu and signaling through AKT leads to tumor regrowth. Combining endocrine therapy with EGFR/HER-2/neu inhibitors should be tested in clinical breast cancer, but a more complete blockade of EGFR/HER-2/neu may be optimal. (Cancer Res 2006; 66(16): 8266-73)
This article has been cited by other articles:
|
|
 |
|
  C. J. Creighton, S. Massarweh, S. Huang, A. Tsimelzon, S. G. Hilsenbeck, C. K. Osborne, J. Shou, L. Malorni, and R. Schiff Development of Resistance to Targeted Therapies Transforms the Clinically Associated Molecular Profile Subtype of Breast Tumor Xenografts Cancer Res., September 15, 2008; 68(18): 7493 - 7501. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 T. C. Haddad and D. Yee Of Mice and (Wo)Men: Is This Any Way to Test a New Drug? J. Clin. Oncol., February 20, 2008; 26(6): 830 - 832. [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]
|
|
|
|
|
|
V. C. Jordan and B. W. O'Malley Selective Estrogen-Receptor Modulators and Antihormonal Resistance in Breast Cancer J. Clin. Oncol., December 20, 2007; 25(36): 5815 - 5824. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lopez-Tarruella and R. Schiff The Dynamics of Estrogen Receptor Status in Breast Cancer: Re-shaping the Paradigm Clin. Cancer Res., December 1, 2007; 13(23): 6921 - 6925. [Full Text] [PDF]
|
|
|
|
|
|
J. Bayliss, A. Hilger, P. Vishnu, K. Diehl, and D. El-Ashry Reversal of the Estrogen Receptor Negative Phenotype in Breast Cancer and Restoration of Antiestrogen Response Clin. Cancer Res., December 1, 2007; 13(23): 7029 - 7036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Wang, S. Dahiya, H. Provencher, B. Muir, E. Carney, K. Coser, T. Shioda, X.-J. Ma, and D. C. Sgroi The Prognostic Biomarkers HOXB13, IL17BR, and CHDH Are Regulated by Estrogen in Breast Cancer Clin. Cancer Res., November 1, 2007; 13(21): 6327 - 6334. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Dawood and M Cristofanilli Endocrine resistance in breast cancer: what really matters? Ann. Onc., August 1, 2007; 18(8): 1289 - 1291. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Arpino, C. Gutierrez, H. Weiss, M. Rimawi, S. Massarweh, L. Bharwani, S. De Placido, C. K. Osborne, and R. Schiff Treatment of Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer Xenografts With Multiagent HER-Targeted Therapy J Natl Cancer Inst, May 2, 2007; 99(9): 694 - 705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Massarweh and R. Schiff Unraveling the Mechanisms of Endocrine Resistance in Breast Cancer: New Therapeutic Opportunities Clin. Cancer Res., April 1, 2007; 13(7): 1950 - 1954. [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]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
