Lysyl Oxidase is essential for hypoxia-induced metastasis in breast cancer

Abstract

Hypoxic tumor cells are highly aggressive and often metastatic, however the underlying processes remain unclear. Lysyl oxidase (LOX) is an enzyme essential for the formation of the extracellular matrix. We show that LOX expression is regulated by HIF-1 and is associated with hypoxia in human breast tumors. Our data demonstrate that patients with high LOX expressing tumors, have poor distant metastasis-free and overall survivals. Inhibition of LOX by shRNA, pharmacological inhibitors or by antibody eliminates metastasis in mice with orthotopically grown breast cancer tumors. Mechanistically, secreted LOX is responsible for the invasive properties of hypoxic human breast and cervical cancer cells through a direct effect on focal adhesion kinase activity and cell to matrix adhesion. Furthermore, LOX mediated cell-matrix interactions are required for metastatic growth. Inhibition of LOX expression and/or activity blocks cell movement (even passive), prevents cell migration and invasion of adjacent tissues, and additionally prevents abundant growth at secondary sites. Together these findings provide strong evidence that LOX is essential for hypoxia-induced metastasis in breast cancer patients, and that LOX is a good therapeutic target to prevent and treat metastasis.