The
type II interleukin-4 receptor (IL4R) is expressed in human
breast cancer, and in murine models thereof. It is activated by
interleukin-4 (
IL4), a
cytokine produced predominantly by immune cells. Previously, we showed that expression of IL4Rα, a signaling component of IL4R, mediates enhanced metastatic growth through promotion of
tumor cell survival and proliferation. In lymphocytes, these processes are supported by increased
glucose and
glutamine metabolism, and B lymphocyte survival is dependent upon
IL4/IL4R-induced
glucose metabolism. However, it is unknown whether IL4R-mediated metabolic reprogramming could support
tumor growth. Here, we show that IL4Rα expression increases proliferation thus enhancing primary mammary
tumor growth. In vitro, IL4-enhanced
glucose consumption and
lactate production in 4T1 cells was mediated by IL4Rα. Expression of the
glucose transporter GLUT1 increased in response to
IL4 in vitro, and enhanced GLUT1 expression was associated with the presence of IL4Rα in 4T1 mammary
tumors in vivo. Although
IL4 treatment did not induce changes in
glucose metabolism in MDA-MB-231 human
breast cancer cells, it increased expression of the main
glutamine transporter, ASCT2, and enhanced
glutamine consumption in both MDA-MB-231 and 4T1 cells. Pharmacologic inhibition of
glutamine metabolism with
compound 968 blocked
IL4/IL4Rα-increased cell number in both cell lines. Our results demonstrate that IL4R mediates enhanced
glucose and
glutamine metabolism in 4T1
cancer cells, and that IL4-induced growth is supported by
IL4/IL4R-enhanced
glutamine metabolism in both human and murine
mammary cancer cells. This highlights IL4Rα as a possible target for effective
breast cancer therapy.