Targeting the Leukemia Inhibitory Factor/Leukemia Inhibitory Factor Receptor Axis Reduces the Growth of Inflammatory Breast Cancer by Promoting Ferroptosis.

Simple Summary: Inflammatory breast cancer (IBC) is a rare subtype of breast cancer that lacks effective targeted therapies. Alterations in growth factor and cytokine signaling have been associated with the progression of IBC. The LIF (leukemia inhibitory factor)/LIFR (leukemia inhibitory factor receptor) cytokine signaling pathway has been linked to the progression of a variety of cancers; however, its importance in IBC has yet to be determined and was investigated in this study. The reduction in LIFR levels using siRNA significantly diminished the proliferation and invasion of IBC cells. The pharmacological inhibition of LIFR using EC359 significantly decreased the cell viability, clonogenicity, and invasive potential of IBC cells, inhibited LIF/LIFR downstream signaling, and enhanced apoptosis. Mechanistic studies revealed that EC359 primarily induced ferroptosis and effectively inhibited the growth of IBC xenograft tumors. Our research indicates that LIFR inhibition facilitates ferroptosis-mediated cell death in IBC, positioning LIFR inhibitors as a possible targeted therapy for IBC. Background: Inflammatory breast cancer (IBC) is a rare subtype of breast cancer accounting for 7% of breast cancer-related fatalities. There is an urgent need to develop new targeted treatments for IBC. The progression of IBC has been associated with alterations in growth factor and cytokine signaling; however, the function of the LIF (leukemia inhibitory factor)/LIFR (leukemia inhibitory factor receptor) cytokine pathway in the progression of IBC remains unknown. This study evaluated the role of LIFR signaling and tested the efficacy of the LIFR inhibitor EC359 in treating IBC. Methods: The utility of using LIFR inhibition as a treatment strategy in IBC was tested using cell survival, apoptosis, colony formation, invasion, and pre-clinical KPL4 xenografts. Western blotting, siRNA, RT-qPCR, and lipid peroxidation assays were used to establish the mechanism of EC359 therapy. Results: The reduction in LIFR levels using siRNA markedly decreased growth in colony formation assays and reduced the invasion of IBC cells. Pharmacological inhibition of LIFR with EC359 effectively reduced cell survival and the clonogenic capacity of IBC cells. RT-qPCR assays revealed that EC359 markedly decreased the expression of the LIFR target genes. Western blot analyses confirmed that EC359 treatment suppressed downstream LIF/LIFR signaling pathways and promoted apoptosis. Treatment of cells with the ferroptosis inhibitor Fer-1 negated the capacity of EC359 to induce apoptosis. Mechanistic investigations demonstrated that EC359 predominantly triggered ferroptosis by inhibiting the glutathione antioxidant defense system through the downregulation of Glutathione peroxidase 4 (GPX4) levels. EC359 (5 mg/kg/day) was effective in reducing the growth of the IBC KPL4 xenograft tumors. Conclusion: These findings demonstrates that LIFR inhibition promote ferroptosis-mediated cell death in IBC and that EC359 represent novel therapeutic for IBC treatment. [ABSTRACT FROM AUTHOR]

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