title: Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism.
abstract: We have previously shown that lysyl oxidase (LOX) mRNA is up-regulated in invasive breast cancer cells and that catalytically active LOX facilitates in vitro cell invasion. Here we validate our in vitro studies by showing that LOX expression is up-regulated in distant metastatic breast cancer tissues compared with primary cancer tissues. To elucidate the mechanism by which LOX facilitates cell invasion, we show that catalytically active LOX regulates in vitro motility/migration and cell-matrix adhesion formation. Treatment of the invasive breast cancer cell lines, Hs578T and MDA-MB-231, with beta-aminopropionitrile (betaAPN), an irreversible inhibitor of LOX catalytic activity, leads to a significant decrease in cell motility/migration and adhesion formation. Conversely, poorly invasive MCF-7 cells expressing LOX (MCF-7/LOX32-His) showed an increase in migration and adhesion that was reversible with the addition of betaAPN. Moreover, a decrease in activated focal adhesion kinase (FAK) and Src kinase, key proteins involved in adhesion complex turnover, was observed when invasive breast cancer cells were treated with betaAPN. Additionally, FAK and Src activation was increased in MCF-7/LOX32-His cells, which was reversible on betaAPN treatment. Hydrogen peroxide was produced as a by-product of LOX activity and the removal of hydrogen peroxide by catalase treatment in invasive breast cancer cells led to a dose-dependent loss in Src activation. These results suggest that LOX facilitates migration and cell-matrix adhesion formation in invasive breast cancer cells through a hydrogen peroxide-mediated mechanism involving the FAK/Src signaling pathway. These data show the need to target LOX for treatment of aggressive breast cancer.
authors.affiliation: Children's Memorial Research Center, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine at Northwestern University, Chicago, IL 60614, USA.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Payne
authors.forename: Ben
authors.initials: B
authors.lastname: Fogelgren
authors.forename: Angela R
authors.initials: AR
authors.lastname: Hess
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Seftor
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Wiley
authors.forename: Sheri F T
authors.initials: SF
authors.lastname: Fong
authors.forename: Katalin
authors.initials: K
authors.lastname: Csiszar
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Kirschmann
mesh_terms: D000629:Aminopropionitrile / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000556:secondary; D002374:Catalase / Q000494:pharmacology; D002448:Cell Adhesion; D002465:Cell Movement; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D008249:Protein-Lysine 6-Oxidase / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D000629:Aminopropionitrile; D006861:Hydrogen Peroxide; D002374:Catalase; D008249:Protein-Lysine 6-Oxidase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src)