The tumor microenvironment supplies pro-inflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL-4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL-4 signaling with the IL-4Rα antagonist IL-4DM compromised breast cancer cell proliferation, invasion and tumor growth by downregulating MAPK pathway activity. IL-4DM reduced numbers of CD44+/CD24- cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-kB. Enforced expression of DUSP4 drove conversion of metastatic cells to non-metastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties and spawned metastastic capacity. Targeting IL-4 signaling sensitized breast cancer cells to anti-cancer therapy and strengthened immune responses by enhancing the number of IFN-γ-positive cytotoxic T lymphocytes. Our results showed the role of IL-4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies.
- Received November 23, 2016.
- Revision received April 7, 2017.
- Accepted April 7, 2017.
- Copyright ©2017, American Association for Cancer Research.