IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition

M. Gaggianesi, A. Turdo, A. Chinnici, E. Lipari, T. Apuzzo, A. Benfante, S. Di Franco, S. Meraviglia, E. Lo Presti, F. Dieli, V. Caputo, G. Militello, S. Vieni, G. Stassi, M. Todaro, Isabella Sperduti

Research output: Contribution to journalArticlepeer-review

Abstract

The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Ralpha antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44+/CD24- cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-kappaB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFNgamma-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies. Cancer Res; 77(12); 3268-79. (c)2017 AACR.
Original languageEnglish
Pages (from-to)3268-3279
Number of pages12
JournalCancer Research
Volume77
Issue number12
DOIs
Publication statusPublished - Jun 15 2017

Fingerprint Dive into the research topics of 'IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition'. Together they form a unique fingerprint.

Cite this