Macrophage migration inhibitory factor (MIF):A novel therapeutic target against aggressive breast cancer

Abstract

Triple negative breast cancer (TNBC), defined as loss of estrogen, progesterone and Her2 receptors, is a subtype of breast cancer with worse prognosis and poor survival rate. Increased inflammation further reduces the TNBC patient survival. Macrophage migration inhibitory factor (MIF) is a pro‐inflammatory molecule known to enhance breast cancer progression and metastasis. However, not much is known about the role of MIF in TNBC progression and metastasis. MIF interacts with various oncogenic molecules and signaling pathways. Therefore, targeting MIF might be a promising strategy to inhibit TNBC progression and metastasis. Here we report that CPSI‐1306, a small molecule inhibitor specific to MIF, possesses the ability to target TNBC cell in vitro by inducing apoptosis. The mechanistic studies revealed that CPSI‐1306 induces apoptosis by enhancing reactive oxygen species (ROS), mitochondria membrane potential alteration, cytochrome C release and activation of Caspases. In addition, CPSI‐1306 also inhibits cell survival and apoptosis signaling molecules, including AKT, PDK and RAF expression. Next, we analyzed the clinical utility of CPSI‐1306 using mouse MVT‐1 cells derived orthotopic and human MDA‐MB‐231 cells derived xenograft TNBC mouse models. The oral treatment of tumor bearing mice with CPSI‐1306 significantly inhibited TNBC growth and metastasis to the lungs in a dose dependent manner. The histological analysis of tumors showed higher number of apoptotic cells in CPSI‐1306 treated tumors compared to vehicle controls. We also observed an association of higher MIF mRNA expression with poor patient survival, including TNBC, by using publically available datasets. These results suggest that CPSI‐1306 induces cell death in TNBC cells via activating ROS and mitochondria‐mediated apoptosis and significantly inhibits TNBC growth and metastasis in pre‐clinical TNBC mouse models.Support or Funding InformationDOD, Breakthrough AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.