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  • Title: Growth effect of neutrophil elastase on breast cancer: favorable action of sivelestat and application to anti-HER2 therapy.
    Author: Nawa M, Osada S, Morimitsu K, Nonaka K, Futamura M, Kawaguchi Y, Yoshida K.
    Journal: Anticancer Res; 2012 Jan; 32(1):13-9. PubMed ID: 22213283.
    Abstract:
    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.
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