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

Thomas J. Rogers, Jessica L. Christenson, Lisa I. Greene, Kathleen I. O'Neill, Michelle M. Williams, Michael A. Gordon, Travis Nemkov, Angelo D'Alessandro, Greg D. Degala, Jimin Shin, Aik Choon Tan, Diana M. Cittelly, James R. Lambert, Jennifer K. Richer

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


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 þ ) breast cancer. In normal epithelial cells and ER þ 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 þ 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.

Original languageEnglish
Pages (from-to)30-41
Number of pages12
JournalMolecular Cancer Research
Issue number1
Publication statusPublished - 2019 Jan 1

ASJC Scopus subject areas

  • Medicine(all)


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