Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression

Mol Cancer Res. 2019 Jan;17(1):30-41. doi: 10.1158/1541-7786.MCR-18-0246. Epub 2018 Sep 13.


Tryptophan-2,3-dioxygenase (TDO2), a rate-limiting enzyme in the tryptophan catabolism pathway, is induced in triple-negative breast cancer (TNBC) by inflammatory signals and anchorage-independent conditions. TNBCs express extremely low levels of the miR-200 family compared with estrogen receptor-positive (ER+) breast cancer. In normal epithelial cells and ER+ breast cancers and cell lines, high levels of the family member miR-200c serve to target and repress genes involved in epithelial-to-mesenchymal transition (EMT). To identify mechanism(s) that permit TNBC to express TDO2 and other proteins not expressed in the more well-differentiated ER+ breast cancers, miRNA-200c was restored in TNBC cell lines. The data demonstrate that miR-200c targeted TDO2 directly resulting in reduced production of the immunosuppressive metabolite kynurenine. Furthermore, in addition to reversing a classic EMT signature, miR-200c repressed many genes encoding immunosuppressive factors including CD274/CD273, HMOX-1, and GDF15. Restoration of miR-200c revealed a mechanism, whereby TNBC hijacks a gene expression program reminiscent of that used by trophoblasts to suppress the maternal immune system to ensure fetal tolerance during pregnancy. IMPLICATIONS: Knowledge of the regulation of tumor-derived immunosuppressive factors will facilitate development of novel therapeutic strategies that complement current immunotherapy to reduce mortality for patients with TNBC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kynurenine / biosynthesis
  • Kynurenine / genetics
  • Kynurenine / immunology
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / immunology
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology
  • Tryptophan / metabolism*
  • Tryptophan Oxygenase / genetics
  • Tryptophan Oxygenase / metabolism


  • MIRN200 microRNA, human
  • MicroRNAs
  • Kynurenine
  • Tryptophan
  • Tryptophan Oxygenase