The Role of Lysyl Oxidase in Breast Cancer Cell Motility

Lysyl oxidase (LOX) was originally reported as a copper-dependent amine oxidase that catalyzes the covalent cross-linking of collagens and elastins within the extracellular matrix. However, recent research has demonstrated that LOX may have a role within the cell in addition to its classical extracellular function. LOX has been localized within the nucleus and cytoplasm of various cell types and has been shown to have a role in cell growth/differentiation, motility/migration, and gene transcription. Our laboratory has previously demonstrated that LOX facilitates breast cancer cell invasion. The work presented here reveals the molecular mechanisms underlying LOX regulation of cell motility/migration in invasive breast cancer cells. We demonstrate that LOX is expressed within the nucleus and cytoplasm of breast cancer tissues and facilitates cell motility through changes in cell-matrix adhesion and actin filament polymerization. Specifically, LOX regulates motility via the FAK/Src signaling complex, two key proteins involved in cell-matrix adhesion and cell migration. Furthermore, LOX regulates actin filament formation and the Rho family of GTPases through the p130Cas/Crk/DOCK180 signaling pathway, a signaling complex downstream of the FAK/Src pathway, further indicating a role for LOX in breast cancer cell motility. Moreover, LOX regulates this pathway through a hydrogen peroxide-mediated mechanism. Finally, we demonstrate that a hypoxic environment which is known to increase cancer cell motility, invasion, and metastasis, induces LOX expression in poorly invasive breast cancer cells that normally do not express LOX. Reoxygenation of these cells leads to a significant increase in LOX activity, leading to a concomitant increase in cell migration and Src activation. Taken together, these results demonstrate that LOX can be regulated through hypoxia and, once activated in breast cancer cells, can increase cell migration through the FAK/Src signaling pathway.