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Interleukin‐like EMT Inducer ILEI mediates breast cancer stem cell formation and tumorigenesis through LIF receptor signaling

During the epithelial‐mesenchymal transition (EMT), cells undergo a switch from a polarized, epithelial state to a more fibroblastic and mesenchymal phenotype. This process is associated with the formation of highly tumorigenic cancer stem cells (CSC). Our lab has identified a regulatory mechanism by which Transforming Growth Factor‐β (TGFβ) induces EMT at the translational step of gene expression. Among gene products controlled by this post‐translational mechanism is the cytokine Interleukin‐like EMT Inducer (ILEI), a secreted factor belonging to the FAM3 family that is involved in EMT induction and tumorigenesis. The biochemical mechanism of the ILEI signaling and identification of an ILEI receptor has remained elusive. Preliminary studies from our lab indicate that modulation of ILEI in several cell lines results in altered stemness potential, giving insight into the possible role of ILEI in the formation of CSCs. The basis of this study aims to investigate the mechanism of the ILEI signaling pathway and its contribution to CSC formation. In order to identify potential ILEI binding partners, we utilized yeast two‐hybrid screening and observed that ILEI interacts with the 190kD leukemia inhibitory factor receptor (LIFR). LIFR serves as a signaling platform for several cytokine ligands and forms intricate complexes with an array of other ligand‐specific co‐receptors during its activation. Our data indicates that ILEI functions through LIFR, inducing downstream CSC phenotypes by activating PI3k/Akt and Jak/STAT signaling pathways. Insight into the TGFβ/ILEI/LIFR pathway may serve as a platform for development of a novel targeted therapy against metastatic breast cancer.