Expression of epidermal growth factor receptor or ErbB3 facilitates geldanamycin-induced down-regulation of ErbB2.
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.
Pedersen
Nina Marie
NM
Institute of Pathology, Faculty of Medicine, University of Oslo, Oslo, Norway.
Breen
Kamilla
K
Rødland
Marianne Skeie
MS
Haslekås
Camilla
C
Stang
Espen
E
Madshus
Inger Helene
IH
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents; D019281:Dimerization; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D003432:Cross-Linking Reagents; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D048051:p38 Mitogen-Activated Protein Kinases; C508053:ERBB2 protein, human; C001277:geldanamycin