Expression of Macrophage Migration Inhibitory Factor in Human Breast Cancer: Association with Nodal Spread

Macrophage migration inhibitory factor (MIF) is known to exert pleiotropic functions including inhibition of macrophage migration, anchoring, and counteraction of the anti‐inflammatory and immunosuppressive activity of glucocorticoids. Ninety‐three primary breast cancer tissues and 64 sera of primary breast cancer patients were analyzed for the expression of MIF. The clinico‐pathological significance of MIF expression was evaluated. It was found that MIF was frequently over‐expressed in primary breast cancer tissues. RT‐PCR and western blotting analysis confirmed that wild‐type MIF is expressed, and immunohistochemical analysis showed that MIF expression was localized at tumor cells as well as stromal cells, including tumor‐associated macrophages. Intra‐tumoral MIF protein concentrations detected by enzyme‐linked immunosorbent assay (ELISA) varied with a median value of 1821 ng/mg protein (range: 8–8126 ng/mg protein), and correlated inversely with nodal involvement (P=0.039). No significant correlation was observed with other clinico‐pathological factors including tumor size, menopausal status and hormone receptors. The circulating level of MIF protein ranged up to 105.7 ng/ml (median: 17.3 ng/ml), and it was also found to correlate inversely with the number of involved nodes (P=0.02). A comparative study with other soluble inflammatory mediators showed that intratumoral levels of MIF were significantly associated with those of interleukin‐1β, suggesting that interactions between tumor cells and tumor‐associated macrophages play an important role in the up‐regulation of MIF. The multifunctional inflammatory/immune mediator MIF was frequently expressed in primary breast cancer, and its expression level was inversely associated with nodal spread. Thus, MIF seems to play a role in tumor‐stroma interactions of primary breast cancers, particularly those with a phenotype of node‐negative or minimal nodal spread.