TGFβ promotes breast cancer stem cell self-renewal through an ILEI/LIFR signaling axis

Abstract

FAM3C/ I nterleukin- l ike E MT I nducer (ILEI) is an oncogenic member of the FAM3 cytokine family and serves essential roles in both epithelial-mesenchymal transition (EMT) and breast cancer metastasis. ILEI expression levels are regulated through a non-canonical TGFβ signaling pathway by 3’-UTR-mediated translational silencing at the mRNA level by hnRNP E1. TGFβ stimulation or silencing of hnRNP E1 increases ILEI translation and induces an EMT program that correlates to enhanced invasion and migration. Recently, EMT has been linked to the formation of breast cancer stem cells (BCSCs) that confer both tumor cell heterogeneity as well as chemoresistant properties. Herein, we demonstrate that hnRNP E1 knockdown significantly shifts normal mammary epithelial cells to mesenchymal BCSCs in vitro and in vivo . We further validate that modulating ILEI protein levels results in the abrogation of these phenotypes, promoting further investigation into the unknown mechanism of ILEI signaling that drives tumor progression. We identify LIFR as the receptor for ILEI, which mediates signaling through STAT3 to drive both EMT and BCSC formation. Reduction of either ILEI or LIFR protein levels results in reduced tumor growth, fewer tumor initiating cells and reduced metastasis within the hnRNP E1 knock-down cell populations in vivo . These results reveal a novel ligand-receptor complex that drives the formation of BCSCs and represents a unique target for the development of metastatic breast cancer therapies.

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Additionally, the FAM3 family of created cytokines, ILEI-induced PDGF-C/PDGF-Rβ [42], or PDGF-Rα activation [43], enhance EMT and aggressiveness by increasing p-STAT3 via Src activation. Repression of hnRNP E1 by non-canonical TGF-β-induced Akt2 increases ILEI expression, and ILEI/ILFR promotes EMT and CSC generation [44,45].…”

Role of STAT3 signaling pathway in breast cancer

“…Kim et al have found that the IL-6/STAT3/ROS pathway can not only promote breast cancer progression and inflammation but also increase the formation of breast cancer stem cells [24]. Moreover, TGFβ-regulated FAM3C/ Interleukin-like EMT Inducer (ILEI), an oncogenic member of the FAM3 cytokine family, can mediate STAT3 signaling pathway to drive breast cancer stem cell formation and promote breast cancer progression [25]. In addition, TNFRSF1A, a gene encoding a transmembrane receptor for TNF-α, can be modulated by STAT3 and promote NF-κB signaling in breast cancer [26].…”

CSF FAM3C- a possible biomarker of Alzheimer’s disease

“…What's more, FAM3C has been shown to be strongly upregulated in several cancers including gastric cancer, melanoma, colon and breast cancer, oral and esophageal squamous cell carcinoma, essential for EMT and metastasis formation, and alter subcellular localization strongly correlating with poor survival [8,9,12,18,19]. It has been indicated that the FAM3C-YY1-HSF1 pathway exerted an important role in TGF β-triggered proliferation and migration of human breast cancer cells [11,20]. In addition, FAM3C is involved in retinal laminar formation in vertebrates and may relate to cell differentiation and proliferation during inner ear embryogenesis [21,22].…”