TGF-β receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms.

Novitskiy SV, Pickup MW, Gorska AE, Owens P, Chytil A, Aakre M, Wu H, Shyr Y, Moses HL
Cancer Discov. 2011 1 (5): 430-41

PMID: 22408746 · PMCID: PMC3297196 · DOI:10.1158/2159-8290.CD-11-0100

We report that IL-17 significantly increases the secretion of CXCL1 and CXCL5 from mammary carcinoma cells, which is downregulated by TGF-β through the type II TGF-β receptor (TβRII). Carcinoma cells with conditional knockout of TβRII (Tgfbr2(KO)) have enhanced sensitivity to IL-17a in the stimulation of chemokine secretion. During polyoma middle T (PyMT) induced tumor progression, levels of Th17 inducing cytokines TGF-β, IL-6, IL-23 were increased in PyMT/Tgfbr2(KO) tumors, which was associated with an increased number of Th17 cells. IL-17 increased the suppressive function of MDSCs on T cells through the upregulation of Arg, IDO, and COX2. Treatment of PyMT/Tgfbr2(KO) mice with anti-IL-17 Ab decreased carcinoma growth and metastatic burden. Analysis of human breast cancer transcriptome databases showed a strong association between IL-17 gene expression and poor outcome in lymph node positive, estrogen receptor negative or luminal B subtypes suggesting potential therapeutic approaches.

MeSH Terms (24)

alpha-Fetoproteins Animals Breast Neoplasms Cell Line, Tumor Chemokines, CXC Cyclooxygenase 2 Disease Progression Female Gene Expression Regulation, Neoplastic Humans Interleukin-17 Ligands Mammary Neoplasms, Experimental Mice Mice, Inbred C57BL Mice, Knockout Monocytes Neoplasm Metastasis Protein-Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta Signal Transduction Th17 Cells Transcriptome

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