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Cancer Discov. 2011 Oct;1(5):430-41. doi: 10.1158/2159-8290.CD-11-0100.

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

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  • 1Department of Cancer Biology, Vanderbilt University, Nashville, TN 37212, USA.

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.

PMID:
22408746
[PubMed - indexed for MEDLINE]
PMCID:
PMC3297196
Free PMC Article

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