A Role for MIF in Tumor Growth and Metastasis

The Macrophage Migration Inhibitory Factor (MIF) is overexpressed in many cancers and the degree of expression correlates with tumor aggressiveness. Sulforaphane (SFN), a chemopreventive agent prevalent in broccoli, is a reactive compound with the potential to modify protein targets. We determined that SFN covalently modifies MIF and inhibits its enzymatic tautomerase activity with an IC 50 within the concentration range observed in the plasma of human subjects following a broccoli sprout meal. We are using the 4T1 model of breast carcinoma to examine the potential role of MIF in tumor growth and progression. This model recapitulates many aspects of human breast tumor progression, including metastasis to similar target organs. A 4T1 tumor cell line depleted of MIF forms smaller tumors than the MIF expressing control, and is reduced in its ability to metastasize to the lung. Reconstitution of the MIF deficient cells with wild‐type MIF rescues the defect in tumor growth, while a tautomerase‐deficient MIF does not, suggesting that MIF tautomerase activity is important for its ability to promote tumor growth. Importantly, the MIF dependent growth differences are only manifested in vivo , suggesting that MIF may be contributing to the interaction between the tumor and the host immune response. We are currently working to characterize a leukocyte population whose recruitment is compromised in MIF depleted tumors.