HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: Implications for HER2-targeted antibody therapy

摘要: We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression in MCF-7 T-47D breast cancer cells that endogenously express low levels resulted elevated expression VEGF IL-8 decreased TSP-1. Inhibition with a humanized anti-HER2 antibody (trastuzumab, or Herceptin) retrovirus-mediated small interfering RNA against (siHER2) expression, but increased TSP-1 BT474 high HER2. These vitro results were further evaluated by treatment xenografts immunosuppressed mice trastuzumab. Trastuzumab inhibited microvascular density associated downregulation upregulation expression. Inhibiting PI3K-AKT pathway AKT1 overexpession did not increase A p38 kinase inhibitor, SB203580, instead blocked activator, MKK6, stimulated sustained activation SB203580 attenuated induced therefore influences equilibrium between pro- factors via distinct pathways. inhibits angiogenesis tumor growth, at least part, through HER2-p38-TSP-1 inhibition HER2-PI3K-AKT-VEGF/IL-8 pathway.