Abstract
Triple-negative breast cancer (TNBC), defined as loss of estrogen, progesterone, and Her2 receptors, is a subtype of highly aggressive breast cancer with worse prognosis and poor survival rate. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine aberrantly expressed in many solid tumors and known to promote tumor progression and metastasis. However, its role in TNBC progression and metastasis is unexplored. Here we have shown that in TNBC patients, MIF expression was significantly enriched in the tumor compared to adjacent normal tissue. Using publically available patient datasets, we showed that MIF overexpression correlates with worse survival in TNBC compared to other hormonal status. Orthotopic implantation of TNBC cells into MIF knockout mice showed reduced tumor growth compared to wild-type mice. In addition, we have shown that MIF downregulation inhibits TNBC growth and progression in a syngeneic mouse model. We further showed that CPSI-1306, a small-molecule MIF inhibitor, inhibits the growth of TNBC cells in vitro. Mechanistic studies revealed that CPSI-1306 induces intrinsic apoptosis by alteration in mitochondrial membrane potential, cytochrome c (Cyt c) release, and activation of different caspases. In addition, CPSI-1306 inhibits the activation of cell survival and proliferation-related molecules. CPSI-1306 treatment also reduced the tumor growth and metastasis in orthotopic mouse models of mammary carcinoma. CPSI-1306 treatment of tumor-bearing mice significantly inhibited TNBC growth and pulmonary metastasis in a dose-dependent manner. Histological analysis of xenograft tumors revealed a higher number of apoptotic cells in CPSI-1306-treated tumors compared to vehicle controls. Our studies, for the first time, show that MIF overexpression in TNBC enhances growth and metastasis. Taken together, our results indicate that using small molecular weight MIF inhibitors could be a promising strategy to inhibit TNBC progression and metastasis.
Highlights
Despite extensive efforts to develop effective therapies against breast cancer, it remains the leading cause of mortality of women around the world[1]
We detected a significantly increased expression of migratory inhibitory factor (MIF) in Triple-negative breast cancer (TNBC) patient samples compared to adjacent normal controls (Fig. 1a)
We further evaluated the expression of MIF in breast cancer patients using publically available datasets
Summary
Despite extensive efforts to develop effective therapies against breast cancer, it remains the leading cause of mortality of women around the world[1]. Official journal of the Cell Death Differentiation Association. Charan et al Cell Death and Disease (2020)11:774 develop novel therapies against highly aggressive and metastatic TNBC. TNBC with an inflammatory phenotype is associated with a poorer prognosis. The exact role of inflammatory molecules in promoting TNBC is yet not defined. MIF is known to bind with the CD74 receptor to activate several inflammatory and survival pathways such as MAPK and PI3K/Akt[7], but the exact molecular mechanism is not fully understood. CD74 or MIF blockade reduced the aggressiveness of invasive breast cancer cells[8]
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