TGF-β Receptor II Loss Promotes Mammary Carcinoma Progression by Th17-Dependent Mechanisms

Sergey V. Novitskiy, Michael W. Pickup, Agnieszka E. Gorska, Philip Owens, Anna Chytil, Mary Aakre, Huiyun Wu, Yu Shyr, Harold L. Moses

研究成果: Article

74 引文 斯高帕斯(Scopus)

摘要

We report that interleukin (IL)-17 significantly increases the secretion of CXC chemokine ligand 1 and 5 (CXCL1/5) from mammary carcinoma cells, and that stimulated secretion of CXCL1/5 by IL-17 is down-regulated 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, and 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 myeloid-derived suppressor cells (MDSC) on T cells through the up-regulation of Arg, IDO, and cyclooxygenase-2. Treatment of PyMT/Tgfbr2 KO mice with anti-IL-17 Ab decreased carcinoma growth and metastatic burden. Analysis of human breast cancer transcriptome databases demonstrated 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. Significance: TGF-β signaling is a major tumor suppressor pathway and is therefore difficult to target therapeutically. Understanding the downstream effects of abrogation of TGF-β signaling in tumor cells may identify processes that can be targeted therapeutically. We present data indicating that targeting IL-17 signaling, a pathway that is greatly enhanced by loss of TGF-β signaling, could provide a therapeutic benefit. Analysis of human databases indicated a specific group of patients in whom treatment could be more efficient.

原文English
頁(從 - 到)430-441
頁數12
期刊Cancer Discovery
1
發行號5
DOIs
出版狀態Published - 2011 十月 1

All Science Journal Classification (ASJC) codes

  • Oncology

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    Novitskiy, S. V., Pickup, M. W., Gorska, A. E., Owens, P., Chytil, A., Aakre, M., Wu, H., Shyr, Y., & Moses, H. L. (2011). TGF-β Receptor II Loss Promotes Mammary Carcinoma Progression by Th17-Dependent Mechanisms. Cancer Discovery, 1(5), 430-441. https://doi.org/10.1158/2159-8290.CD-11-0100