The lysyl oxidase inhibitor, beta-aminopropionitrile, diminishes the metastatic colonization potential of circulating breast cancer cells.
Lysyl oxidase (LOX), an extracellular matrix remodeling enzyme, appears to have a role in promoting breast cancer cell motility and invasiveness. In addition, increased LOX expression has been correlated with decreases in both metastases-free, and overall survival in breast cancer patients. With this background, we studied the ability of beta-aminopropionitrile (BAPN), an irreversible inhibitor of LOX, to regulate the metastatic colonization potential of the human breast cancer cell line, MDA-MB-231. BAPN was administered daily to mice starting either 1 day prior, on the same day as, or 7 days after intracardiac injection of luciferase expressing MDA-MB-231-Luc2 cells. Development of metastases was monitored by in vivo bioluminescence imaging, and tumor-induced osteolysis was assessed by micro-computed tomography (microCT). We found that BAPN administration was able to reduce the frequency of metastases. Thus, when BAPN treatment was initiated the day before, or on the same day as the intra-cardiac injection of tumor cells, the number of metastases was decreased by 44%, and 27%, and whole-body photon emission rates (reflective of total tumor burden) were diminished by 78%, and 45%, respectively. In contrast, BAPN had no effect on the growth of established metastases. Our findings suggest that LOX activity is required during extravasation and/or initial tissue colonization by circulating MDA-MB-231 cells, lending support to the idea that LOX inhibition might be useful in metastasis prevention.
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
Alla
A
Bondareva
Charlene M
CM
Downey
Fabio
F
Ayres
Wei
W
Liu
Steven K
SK
Boyd
Benedikt
B
Hallgrimsson
Frank R
FR
Jirik
D000629:Aminopropionitrile / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009360:Neoplastic Cells, Circulating / Q000187:drug effects*; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors*; D055114:X-Ray Microtomography
D000970:Antineoplastic Agents; D000629:Aminopropionitrile; D008249:Protein-Lysine 6-Oxidase