Growth effect of neutrophil elastase on breast cancer: favorable action of sivelestat and application to anti-HER2 therapy.
OBJECTIVE
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.


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.


CONCLUSIONS
Combinatorial use of sivelestat and trastuzumab might be a novel therapeutic strategy for HER2-positive breast cancer.
Department of Surgical Oncology, Gifu University School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Japan.
Masahito
M
Nawa
Shinji
S
Osada
Kasumi
K
Morimitsu
Kenichi
K
Nonaka
Manabu
M
Futamura
Yoshihiro
Y
Kawaguchi
Kazuhiro
K
Yoshida
D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D005998:Glycine; D019272:Leukocyte Elastase; D018719:Erb-b2 Receptor Tyrosine Kinases; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D016211:Transforming Growth Factor alpha; D000068878:Trastuzumab; C069195:sivelestat