Abstract
Overexpression of the epidermal growth factor receptor (EGFR), ErbB2, and ErbB3 promotes growth and antiapoptotic signaling. Overexpression of ErbB2 in breast cancer is associated with poor clinical outcome, and ways of down-regulating ErbB2 are important as therapeutic approaches. In contrast to EGFR, ErbB2 has been shown to be endocytosis deficient. However, down-regulation of ErbB2 can be induced by incubation of cells with geldanamycin and geldanamycin derivatives, counteracting the stabilizing function of heat shock protein 90 on ErbB2. In the present study, we have made use of stably transfected isogenic cell lines expressing ErbB2 only or ErbB2 together with EGFR and/or ErbB3. We now show that whereas ErbB2 can be down-regulated by incubation with geldanamycin in cells expressing ErbB2 only, the rate of geldanamycin-induced down-regulation increases significantly when the cells additionally express EGFR and/or ErbB3. This increase does, however, not correlate with activation/phosphorylation of ErbB2. The potential of heterodimer formation in ErbB2-positive breast cancer cells could thus turn out to be prognostically predictive with respect to outcome of treatment with geldanamycin derivatives.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibiotics, Antineoplastic / pharmacology*
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Apoptosis / drug effects
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Benzoquinones / pharmacology*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Proliferation / drug effects
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Cross-Linking Reagents
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Dimerization
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Down-Regulation
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Flow Cytometry
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Gene Expression Regulation, Neoplastic
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Immunoblotting
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Immunoenzyme Techniques
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Immunoprecipitation
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Lactams, Macrocyclic / pharmacology*
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Phosphorylation / drug effects
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Receptor, ErbB-2 / antagonists & inhibitors
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism*
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Receptor, ErbB-3 / genetics
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Receptor, ErbB-3 / metabolism*
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Signal Transduction / drug effects
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Tumor Cells, Cultured
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antibiotics, Antineoplastic
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Benzoquinones
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Cross-Linking Reagents
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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Epidermal Growth Factor
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ERBB2 protein, human
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ErbB Receptors
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Receptor, ErbB-2
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Receptor, ErbB-3
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p38 Mitogen-Activated Protein Kinases
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geldanamycin