Breast-to-brain metastasis is a devastating disease complication for which there are currently few treatment options. Among breast cancer subtypes, patients with triple-negative breast cancer (TNBC) and HER2+ breast cancer experience elevated rates of brain metastasis. The cytokines IL4 and IL13 are overexpressed by many human solid tumors. Both are associated with invasive and metastatic phenotypes; IL13 is additionally consequential in primary brain tumors. These cytokines signal through type I (IL4 only) and type II (IL4/IL13) IL4 receptors (IL4R). Importantly, expression of type II IL4R correlates with poor patient prognosis in basal-like (i.e., triple-negative) breast cancer, and HER2+ tumors display elevated type II IL4R expression. Our laboratory has shown that genetic loss of IL4R signaling in tumor cells attenuates lung and liver metastasis in mice. Additionally, we recently identified a role for IL4R signaling in modulating glycosylation in tumor cells. We hypothesize that IL4R signaling influences TNBC brain metastasis at least in part via modulating glycosylation. In a pilot mouse study, pharmacological blockade of IL4R after intracardiac injection of syngeneic TNBC cells resulted in attenuation of brain metastatic growth and circulating tumor cell burden. We have also observed significant changes in the expression of a sialyltransferase (ST8SIA1) that has been implicated in primary brain tumors, as well as in the abundance of several sialic acid-containing protein species in breast cancer cells following treatment with IL4 or IL13. Further, IL4 stimulation increases the overall glycosylation of several proteins of interest, including a glucose transporter and a glutamine transporter, without altering gene expression. Overall, our data suggest that type II IL4R signaling promotes metastasis, potentially through a mechanism involving protein glycosylation. Blockade of this receptor may be a useful therapeutic approach for patients with breast cancer brain metastases.

Citation Format: Wendy Bindeman, Demond Williams, Ebony Hargrove-Wiley, Barbara Fingleton. Investigating the role of type II IL4 receptor in breast cancer brain metastasis [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 2401.