title: Anti-HER-3 MAbs inhibit HER-3-mediated signaling in breast cancer cell lines resistant to anti-HER-2 antibodies.
abstract: Two members of the EGF receptor family, HER2 and HER3, act as key oncogenes in breast cancer cells. A MAb against HER2, trastuzumab, interferes with HER2 signaling and istherapeutically effective in humans. Here, we explored the biologic effects of an antibody against HER3 (alpha-HER3ECD) in the invasive breast cancer cell lines MCF-7ADR and MDA-MB-468. Pretreating the breast cancer cells with alpha-HER3ECD prior to Heregulin stimulation caused significant reduction of the migratory and proliferative properties. This reduction is due to a substantial decrease in the tyrosine phosphorylation content of HER2 and to a modification of the HER2/HER3 association, which ultimately inhibits the activity of the downstream effectors phosphatidyinositol-3-OH-kinase and c-jun-terminal kinase. Furthermore, HER3 is internalized and not activated by HRG after pretreatment with alpha-HER3ECD. Our data reinforce the notion that HER3 could be a key target in cancer drug design and show the great potential of anti-HER3 antibodies for the therapy of breast cancer and other malignancies characterized by overexpression of HER3.
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Biochemistry, Martinsried, Munich, Germany.
authors.forename: Edward Htun
authors.initials: EH
authors.lastname: van der Horst
authors.forename: Marta
authors.initials: M
authors.lastname: Murgia
authors.forename: Martin
authors.initials: M
authors.lastname: Treder
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D019921:Biotinylation; D001943:Breast Neoplasms / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D020890:Neuregulin-1 / Q000494:pharmacology; D020893:Receptor, ErbB-3 / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D020890:Neuregulin-1; D020893:Receptor, ErbB-3