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IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition
- Source :
- Cancer Research. 77:3268-3279
- Publication Year :
- 2017
- Publisher :
- American Association for Cancer Research (AACR), 2017.
-
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 IL4Rα 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-κB. 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 IFNγ-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. ©2017 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
Blotting, Western
CA 15-3
Breast Neoplasms
03 medical and health sciences
Paracrine signalling
0302 clinical medicine
Breast cancer
Cell Line, Tumor
Tumor Microenvironment
medicine
Humans
skin and connective tissue diseases
Autocrine signalling
Dual-Specificity Phosphatase
Disease Progression
Dual-Specificity Phosphatases
Female
Flow Cytometry
Heterografts
Interleukin-4
Mitogen-Activated Protein Kinase Phosphatases
Oncology
Tumor microenvironment
biology
CD44
Cancer
medicine.disease
030104 developmental biology
030220 oncology & carcinogenesis
Immunology
Cancer cell
biology.protein
Cancer research
Heterograft
Mitogen-Activated Protein Kinase Phosphatase
Breast Neoplasm
Human
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 77
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....1ede0d67230f1a5d7cc53357060e0488