Type II interleukin-4 receptor activation promotes tumor pro-gression in basal breast cancer cells via metabolic and epige-netic modulation

Interleukin-4 (IL4) is a Th2 cytokine that can signal through two different receptors, one of which – the type II receptor - is overexpressed by various cancer cells. Previously we have shown that type II IL4 receptor signaling increases proliferation and metastasis in mouse models of breast cancer, as well as increasing glucose and glutamine metabolism. Here we expand on those findings to determine mechanistically how IL4 signaling links glucose metabolism and histone acetylation to drive proliferation in the context of triple-negative breast cancer (TNBC). We used a combination of cellular, biochemical and genomics approaches to interrogate TNBC cell lines, which represent a cancer type where high expression of the type II IL4 receptor is linked with reduced survival. Our results indicate that type II IL4 receptor activation leads to increased glucose uptake, Akt and ACLY activation,and histone acetylation in TNBC cell lines. Inhibition of glucose uptake through deletion of Glut1 ablates IL4-induced proliferation. Additionally, pharmacological inhibition of histone acetyltransferase P300 attenuates IL4-mediated gene expression, and proliferationin vitro. Our work elucidates a role for type II IL4 receptor signaling in promoting TNBC progression, and highlights type II IL4 signaling as well as histone acetylation as possible targets for therapy.