The Roles of IL13RA1 and IL13RA2 in Brain Metastatic Triple-Negative Breast Cancer

Abstract

Despite recent advances in clinical care, triple-negative breast cancer (TNBC) is still associated with poor patient prognosis and elevated risk of metastasis, especially to the brain, which is a major therapeutic challenge. The cytokines IL4 and IL13 are overexpressed by many solid tumors and are associated with invasive and metastatic phenotypes. On epithelial cancer cells, these cytokines signal through the type II IL4 receptor (IL4R; composed of IL4Rα and IL13RA1) via STAT6. IL13 additionally signals through IL13RA2, an understudied receptor predominantly characterized as a negative regulator of IL13 signaling. IL13RA2 is highly expressed on primary brain tumors and associated with aggressive tumor characteristics in some cancers. However, the biological function of IL13RA2 in cancer and its relationship with patient prognosis remain controversial. We sought to define the roles of IL13RA1 and IL13RA2 in TNBC cell behavior and metastasis, with particular attention to brain metastasis. We generated several IL13RA1- and IL13RA2-deficient TNBC cell line models using CRISPR/Cas9 and shRNA technology. Unexpectedly, we found that IL13RA1/2-deficient TNBC cells displayed survival and, to a lesser extent, growth advantages in vitro. Notably, this phenotype was most striking in IL13RA2-deficient cells. Following intracardiac injection, IL13RA2-deficient TNBC cells displayed significantly enhanced metastasis, while IL13RA1-deficient derivatives trended in the same direction. Further, low IL13RA2 expression correlates with shorter survival and presence of brain metastases in patients with breast cancer. RNA-Seq and mechanistic studies revealed that IL13RA2-deficient TNBC cells display enhanced AKT and NF-κB signaling and are sensitized to inhibition of either pathway, but especially AKT. Finally, we present preliminary studies characterizing IL4/IL13-stimulated glycosylation in TNBC cells, with particular attention to the sialyltransferase ST8SIA1, a known STAT6 target. Our data suggest that loss of IL13RA2, and possibly also IL13RA1, has pro-tumorigenic and pro-metastatic consequences in TNBC. IL13RA2 inhibition, which is being explored as a therapeutic option in other tumor contexts, should be avoided in TNBC, but AKT inhibitors could be a therapeutic option for patients with IL13RA2-low tumors.