Molecular and Cellular Pathobiology IL4 Receptor ILR4a Regulates Metastatic Colonization by Mammary Tumors through Multiple Signaling Pathways

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 IL4Ra, 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 IL4Ra "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 IL4Ra 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 IL4Ra knockdown tumor metastases were associated with limited outgrowth, supporting roles for Akt and Erk activation in mediating the tumor-promoting effects of IL4Ra. Collectively, our results offer a preclinical proof-of-concept for targeting IL4/IL4Ra signaling as a therapeutic strategy to limit breast cancer metastasis. Cancer Res; 74(16); 4329–40. 2014 AACR.