ABSTRACT: Triple-negative breast cancer is characterized by absence of oestrogen receptor, progesterone receptor, and a lack of HER2 amplification and is associated with poor patient prognosis and high rates of distant metastasis. These patients are at elevated risk of brain metastasis, which remains a major therapeutic challenge. IL13RA2, a high-affinity receptor for IL13, is highly expressed in primary brain cancers, many extracranial solid tumours, and in lung- and brain-seeking metastatic variant cell lines. However, the relationship between IL13RA2 and patient prognosis is variable, and the biological function of this receptor in cancer remains controversial. We sought to define the role of IL13RA2 in TNBC growth and metastasis, with an emphasis on breast-to-brain metastasis. We identified a positive correlation between elevated IL13RA2 mRNA expression and overall survival in a publicly available dataset of basal-like breast cancer patients. We generated IL13RA2-CRISPR knockout derivatives of the human brain-seeking breast cancer cell line MDA231BrM2 as well as murine 4T1 cells and evaluated changes in gene expression, proliferation, survival, and metastatic growth in vivo. We find that both IL13RA2-deficient models demonstrate enhanced survival and proliferation in vitro, as well as augmented metastatic tumour growth and worsened survival in intracardiac models of brain metastasis. Mechanistically, we observe increased AKT and NF-κB signalling in IL13RA2-deficient cells, which renders these cells highly sensitive to inhibition of AKT. We conclude that, in triple negative breast cancer, loss of IL13RA2 in tumour cells is strongly pro-metastatic, antiapoptotic, and pro-proliferative. These phenotypes are mediated through the AKT and NF-κB pathways. IL13RA2-deficient cells are highly vulnerable to AKT inhibition, which may represent a clinically useful vulnerability for patients with IL13RA2-low tumours. However, our data suggest that inhibition of IL13RA2, though promising in other tumour contexts, may be deleterious in metastatic triple-negative breast cancer.
