Role of galectin-3 in breast cancer metastasis: Involvement of nitric oxide

We investigated the role of galectin-3 in metastasis of human breast carcinoma BT549 cells using the experimental liver metastasis model. Underlying mechanisms were then elucidated using the liver/tumor coculture and cell culture systems. After intrasplenic injection, galectin-3 cDNA transfected BT549 cells (BT549_{gal-3 wt}) formed metastatic colonies in the liver, while galectin-3 null BT549 cells (BT549_par) did not, demonstrating that galectin-3 enhances metastatic potential. More than 90% of BT549_{gal-3 wt} cells survived after 24 hours-co-culture with the liver fragments isolated following ischemia treatment. In contrast, more than half of BT549_par cells showed metabolic death following co-culture with the liver fragments. When the liver from inducible nitric oxide synthase (iNOS) knockout mice was used, no cytotoxicity to BT549_par cells was observed. Thus, iNOS exerts cytotoxicity on BT549_par cells and galectin-3 can protect against iNO-Sinduced cytotoxicity. BT549_{gal-3 wt} also exhibited enhanced survival against peroxynitrite (up to 400 μmol/L) in vitro. A single mutation in the NWGR motif of galectin-3 obliterated both metastatic capability and cell survival, indicating that the antiapoptotic function of galectin-3 is involved in enhanced metastasis. In conclusion, galectin-3 enhances the metastatic potential of BT549 cells through resistance to the products of iNOS, possibly through its bcl-2-like antiapoptotic function.