TY - JOUR T1 - Growth Effect of Neutrophil Elastase on Breast Cancer: Favorable Action of Sivelestat and Application to Anti-HER2 Therapy JF - Anticancer Research JO - Anticancer Res SP - 13 LP - 19 VL - 32 IS - 1 AU - MASAHITO NAWA AU - SHINJI OSADA AU - KASUMI MORIMITSU AU - KENICHI NONAKA AU - MANABU FUTAMURA AU - YOSHIHIRO KAWAGUCHI AU - KAZUHIRO YOSHIDA Y1 - 2012/01/01 UR - http://ar.iiarjournals.org/content/32/1/13.abstract N2 - Aim: To investigate the relation between neutrophil elastase (NE) and proliferation of breast cancer cells and whether the NE inhibitor sivelestat could both contribute and be applied to therapy for anti-epithelial growth factor receptor 2 (HER2)-positive breast cancers. Materials and Methods: The proliferation or inhibition of breast cancer cell line SKBR-3 by each agent was evaluated by methylthiazole tetrazolium (MTT) assay. Signal transduction and expression of signaling molecules were evaluated by Western blot analysis. Results: The auto tumor progression mechanism initiated by NE through tumor growth factor-α (TGF-α) was present in breast cancer cells, and this mechanism was intensively suppressed by sivelestat. The effect of trastuzumab was suppressed, and trastuzumab-induced HER2 down-regulation was impaired by TGF-α. TGF-α not only promoted cell proliferation as a ligand but also enhanced resistance to trastuzumab by impairing HER2 down-regulation. Furthermore, combined use of trastuzumab and sivelestat suppressed cell proliferation more intensively than either drug alone and did not provoke impairment by TGF-α of HER2-induced down-regulation. Conclusion: Combinatorial use of sivelestat and trastuzumab might be a novel therapeutic strategy for HER2-positive breast cancer. ER -