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Lysyl oxidase (LOX) was initially reported as a copper-dependent amine oxidase responsible for the catalysis of collagen and elastin cross-linking within the extracellular matrix. However, recent work has demonstrated that LOX may have many other roles, including at the intracellular level. Catalytically active LOX has been localized in the nucleus and cytoplasm of fibroblasts and vascular smooth muscle cells and has been shown to have a role in gene transcription regulation and motility/migration. We have demonstrated that LOX mRNA is up-regulated in invasive breast cancer cells, compared to poorly invasive tumor cells, and facilitates in vitro motility/migration and subsequent invasion of breast cancer cell lines. Therefore, we hypothesize that LOX facilitates intracellular signaling in invasive breast cancer cells causing an induction in tumor progression. Treatment of the invasive breast cancer cell line, Hs578T, with β-aminopropiontrile (βAPN), an irreversible inhibitor of LOX catalytic activity, leads to a decrease in focal adhesion kinase (FAK) and Src activity. These observed changes in FAK and Src activity were not due to a loss of their protein expression. Furthermore, a decrease in cell adhesion formation was observed in Hs578T cells treated with βAPN, possibly caused by the loss of FAK/Src activity. Additionally, loss of LOX catalytic activity in invasive breast cancer cells leads to a decrease in Rac activity with no changes in Rac protein expression. Finally, inhibition of LOX catalytic activity with βAPN treatment leads to a decrease in NFκB activity. Taken together, these results demonstrate that inhibition of LOX catalytic activity leads to a decrease in activity of several key proteins regulating cell adhesion, actin filament formation, and gene transcription regulation. Therefore, LOX appears to facilitate intracellular signaling in invasive breast cancer cells causing subsequent changes in cell motility/migration and invasion. Elucidating the mechanism(s) by which LOX facilitates intracellular signaling could lead to novel therapeutic approaches in the treatment of metastatic breast cancer. Supported in part by DAMD17-99-1-9225 and Eisenberg Scholar Research Award (DAK), and NIH/NCI CA59702 and Order of the Eastern Star Breast Cancer Research Fund (MJCH).

[Proc Amer Assoc Cancer Res, Volume 46, 2005]