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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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TGF-β receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms

Sergey V Novitskiy1, Michael W Pickup, Agnieszka E Gorska

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

Cancer Discovery
|March 13, 2012
PubMed

Insights

Interleukin-17 (IL-17) promotes mammary carcinoma growth by increasing chemokine secretion and myeloid-derived suppressor cell (MDSC) function. Blocking IL-17 reduced tumor progression and metastasis in mice, suggesting IL-17 as a therapeutic target.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Interleukin-17 (IL-17) plays a complex role in cancer, with dual functions reported in different contexts.
  • Transforming growth factor-beta (TGF-β) signaling, mediated by the TGF-β receptor type II (TβRII), is crucial in regulating immune responses and tumor progression.
  • Myeloid-derived suppressor cells (MDSCs) are key players in tumor immune evasion.

Purpose of the Study:

  • To investigate the role of IL-17 in mammary carcinoma progression, particularly in relation to TGF-β signaling.
  • To determine the impact of IL-17 on MDSC function and its contribution to tumor growth.
  • To evaluate the therapeutic potential of targeting IL-17 in a preclinical model of breast cancer.

Main Methods:

  • Utilized a polyoma middle T (PyMT) induced mouse model of mammary carcinoma with conditional knockout of TβRII (Tgfbr2(KO)).
  • Assessed chemokine secretion (CXCL1, CXCL5) from carcinoma cells in response to IL-17 and TGF-β.
  • Quantified Th17 cell infiltration and analyzed MDSC suppressive function markers (Arg, IDO, COX2).
  • Administered anti-IL-17 antibody treatment to evaluate its effect on tumor growth and metastasis.
  • Correlated IL-17 gene expression with patient outcomes using human breast cancer transcriptome databases.

Main Results:

  • IL-17 significantly enhanced CXCL1 and CXCL5 secretion from mammary carcinoma cells, a process normally downregulated by TGF-β via TβRII.
  • Tgfbr2(KO) carcinoma cells exhibited increased sensitivity to IL-17-induced chemokine secretion.
  • PyMT/Tgfbr2(KO) tumors showed elevated levels of Th17-inducing cytokines and increased Th17 cell infiltration.
  • IL-17 upregulated Arg, IDO, and COX2 in MDSCs, enhancing their suppressive function on T cells.
  • Anti-IL-17 antibody treatment reduced tumor growth and metastatic burden in PyMT/Tgfbr2(KO) mice.
  • High IL-17 gene expression in human breast cancer correlates with poor prognosis in specific subtypes (lymph node positive, ER-negative, luminal B).

Conclusions:

  • IL-17 promotes mammary carcinoma progression by stimulating chemokine production and enhancing MDSC-mediated immunosuppression.
  • The TβRII pathway modulates the response of carcinoma cells to IL-17.
  • Targeting IL-17 represents a promising therapeutic strategy for specific subtypes of human breast cancer.

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