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 DUSP4by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4activated the ERKand 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.

Gaggianesi, M., Turdo, A., Chinnici, A., Lipari, E., Apuzzo, T., Benfante, A., et al. (2017). IL4 primes the dynamics of breast cancer progression via DUSP4 inhibition. CANCER RESEARCH, 77(12), 3268-3279 [10.1158/0008-5472.CAN-16-3126].

IL4 primes the dynamics of breast cancer progression via DUSP4 inhibition

Gaggianesi, Miriam;Turdo, Alice;Lipari, Elisa;Apuzzo, Tiziana;Benfante, Antonina;Di Franco, Simone;Meraviglia, Serena;Lo Presti, Elena;Dieli, Francesco;Caputo, Valentina;Militello, Gabriella;Vieni, Salvatore;Stassi, Giorgio;Todaro, Matilde
2017-01-01

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 DUSP4by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4activated the ERKand 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.
2017
Gaggianesi, M., Turdo, A., Chinnici, A., Lipari, E., Apuzzo, T., Benfante, A., et al. (2017). IL4 primes the dynamics of breast cancer progression via DUSP4 inhibition. CANCER RESEARCH, 77(12), 3268-3279 [10.1158/0008-5472.CAN-16-3126].
File in questo prodotto:
File Dimensione Formato  
Gaggianesi Cancer research 2017.pdf

Solo gestori archvio

Dimensione 1.51 MB
Formato Adobe PDF
1.51 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/245829
Citazioni
  • ???jsp.display-item.citation.pmc??? 30
  • Scopus 42
  • ???jsp.display-item.citation.isi??? 42
social impact