title: IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition.
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.
authors.affiliation: Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Gaggianesi
authors.affiliation: Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Turdo
authors.affiliation: Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Aurora
authors.initials: A
authors.lastname: Chinnici
authors.affiliation: Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lipari
authors.affiliation: Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Apuzzo
authors.affiliation: Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Benfante
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Di Franco
authors.affiliation: Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy.|Department of Biopathology and Biomedical Methodologies, University of Palermo, Palermo, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Meraviglia
authors.affiliation: Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Lo Presti
authors.affiliation: Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy.|Department of Biopathology and Biomedical Methodologies, University of Palermo, Palermo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dieli
authors.affiliation: Department of DIBIMIS, University of Palermo, Palermo, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Caputo
authors.affiliation: Department of Emergency, General Surgery and Organ Transplants, University of Palermo, Palermo, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Militello
authors.affiliation: Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vieni
authors.affiliation: Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
authors.affiliation: Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy. matilde.todaro@gmail.com.|Department of DIBIMIS, University of Palermo, Palermo, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: C508598:IL4 protein, human; D015847:Interleukin-4; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases