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-HER3(ECD)) in the invasive breast cancer cell lines MCF-7 ADR and MDA-MB-468. Pretreating the breast cancer cells with alpha-HER3(ECD) prior to Heregulin stimulation caused significant reduction or 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 riot activated by HRG after pretreatment with ECD alpha-HER3(ECD). 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. (c) 2005 Wiley-Liss, Inc.