Anti-HER-3 MAbs inhibit HER-3-mediated signaling in breast cancer cell lines resistant to anti-HER-2 antibodies.
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.
van der Horst
Edward Htun
EH
Department of Molecular Biology, Max Planck Institute for Biochemistry, Martinsried, Munich, Germany.
Murgia
Marta
M
Treder
Martin
M
Ullrich
Axel
A
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
D000911:Antibodies, Monoclonal; D020890:Neuregulin-1; D020893:Receptor, ErbB-3