IL4, a
cytokine produced mainly by immune cells, may promote the growth of epithelial
tumors by mediating increased proliferation and survival. Here, we show that the type II
IL4 receptor (IL4R) is expressed and activated in human
breast cancer and mouse models of
breast cancer. In metastatic mouse
breast cancer cells, RNAi-mediated silencing of IL4Rα, a component of the IL4R, was sufficient to attenuate growth at metastatic sites. Similar results were obtained with control
tumor cells in IL4-deficient mice. Decreased metastatic capacity of IL4Rα "knockdown" cells was attributed, in part, to reductions in proliferation and survival of
breast cancer cells. In addition, we observed an overall increase in immune infiltrates within IL4Rα knockdown
tumors, indicating that enhanced clearance of knockdown
tumor cells could also contribute to the reduction in knockdown
tumor size. Pharmacologic investigations suggested that IL4-induced
cancer cell colonization was mediated, in part, by activation of Erk1/2, Akt, and mTOR. Reduced levels of pAkt and pErk1/2 in IL4Rα knockdown
tumor metastases were associated with limited outgrowth, supporting roles for Akt and Erk activation in mediating the
tumor-promoting effects of IL4Rα. Collectively, our results offer a preclinical proof-of-concept for targeting
IL4/IL4Rα signaling as a therapeutic strategy to limit
breast cancer metastasis.