Abstract 3035: Proliferation induced by IL4R is regulated via Glut1 activity in metastatic breast cancer

Abstract

Abstract Metabolic reprogramming is a characteristic of all cancers including breast cancer; however, the signaling pathways involved are not fully understood. Altered metabolism, like a shift to aerobic glycolysis, supports cancer cell growth and metastatic behavior. Similarly, immune signals from the tumor microenvironment can promote these same phenotypes and therefore, immune signals likely influence the metabolic state of cancer cells. More specifically, the cytokine interleukin-4 (IL4) promotes increased tumor cell survival, proliferation, and invasion upon stimulation of the type II IL4 receptor alpha (IL4Rα) which is aberrantly expressed on epithelial cancer cells. Previously, we have shown that metastatic mouse mammary cancer cells (4T1) rely on IL4 signaling for colonization of metastatic sites in the lung and liver. Additionally, these cells uptake more glucose when treated with IL4 in vitro. Here, we investigated the significance of glucose consumption on pro-tumorigenic phenotypes induced by IL4/IL4Rα. In 4T1 cells, IL4/IL4Rα signaling increased protein expression and global glycosylation of a primary glucose transporter, Glut1. In human metastatic breast cancer cells (MDA-MB-231), CRISPR-mediated knockout (KO) of Glut1 significantly reduced basal and IL4-induced glucose consumption when assayed by 2-NBDG uptake, a fluorescently labeled glucose analog. Glut1 KO reversed the proliferative effects of IL4/IL4Rα activation on human cancer cells in vitro. Glut1 depletion attenuated tumor cell dependence on glucose consumption as shown by decreased expression of Hexokinase-2, a rate-limiting enzyme in glycolysis. In addition, KO cells have elevated levels of the glutamine transporter, ASCT2, that are further enhanced by IL4 treatment which suggest a greater reliance on glutamine albeit, insufficient for cell expansion supported by IL4/IL4Rα stimulation. Our data indicate that IL4-induced glucose consumption supports the increased metabolic activity necessary for cancer cell proliferation. Targeting the IL4/IL4Rα signaling axis could be a therapeutic strategy to hinder tumor-associated metabolism and reduce tumor burden at primary and metastatic sites. Citation Format: Ebony Hargrove-Wiley, Daniel Valent, Demond Williams, Wendy Bindeman, Barbara Fingleton. Proliferation induced by IL4R is regulated via Glut1 activity in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3035.