Abstract A046: Heterogenous nuclear ribonucleoprotein E1 regulates leukemia inhibitory factor receptor (LIFR) expression through FAM3C in mammary epithelial cells

Abstract

Abstract Leukemia inhibitory factor receptor (LIFR) signals through signal transducer and activator of transcription 3 (STAT3), a transcription factor that is associated with poor prognosis due to its overexpression and/or hyperactivity in 40% of breast cancer cases. LIFR has been defined as either a promoter or suppressor of metastasis in mammary carcinoma, and recently we have shown that its expression is significantly upregulated following loss of the RNA-binding protein heterogenous nuclear ribonucleoprotein E1 (hnRNP E1, “E1”). We have further shown that E1 is a regulator of the epithelial-to-mesenchymal transition (EMT) and of differentiation in mammary epithelium. Mechanistically, E1 acts as a tumor suppressor by binding to and inhibiting translation of mRNAs involved in EMT and cellular self-renewal, including the cytokine FAM3C. We have demonstrated that FAM3C binds to LIFR in the extracellular space and activates STAT3. Herein, we characterize induction of LIFR expression in response to FAM3C/LIFR signaling, and show that E1 upregulates LIFR transcription through FAM3C, involving initiation at the LIFR promoter locus. Induction of LIFR expression in mammary epithelial cells has been shown to be associated with tumor initiation, breast cancer stem cells, and metastasis. Additionally, our bioinformatic analysis reveals a signature of transcriptional regulation associated with FAM3C/LIFR interaction. Comparison between RNA-sequencing data from our mouse model of mammary carcinoma and human mammary carcinoma cell lines reveals common biological pathways and potential therapeutic targets. Future directions will be aimed at investigating the effect of modulation of LIFR expression during tumor dissemination in vivo. Citation Format: William S. Streitfeld, Annamarie C. Dalton, Philip H. Howe. Heterogenous nuclear ribonucleoprotein E1 regulates leukemia inhibitory factor receptor (LIFR) expression through FAM3C in mammary epithelial cells [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A046.