Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Cell Line, Tumor
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Chemokines, CXC / genetics
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Chemokines, CXC / metabolism
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Disease Progression
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Interleukin-17 / genetics
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Interleukin-17 / metabolism*
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Ligands
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Monocytes / metabolism
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Neoplasm Metastasis
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Protein Serine-Threonine Kinases / deficiency*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / deficiency*
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction
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Th17 Cells / metabolism*
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Transcriptome
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alpha-Fetoproteins / genetics
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alpha-Fetoproteins / metabolism
Substances
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Chemokines, CXC
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Interleukin-17
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Ligands
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Receptors, Transforming Growth Factor beta
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alpha-Fetoproteins
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alpha-fetoprotein related protein, mouse
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Cyclooxygenase 2
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II