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 journalArticle

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Abstract

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 (ERþ) breast cancer. In normal epithelial cells and ERþ 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 ERþ 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
Volume17
Issue number1
DOIs
Publication statusPublished - 2019 Jan 1

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Triple Negative Breast Neoplasms
Epithelial-Mesenchymal Transition
Tryptophan
Immunosuppression
Immunosuppressive Agents
Estrogens
Breast Neoplasms
Tryptophan Oxygenase
Kynurenine
Cell Line
Trophoblasts
MicroRNAs
Immunotherapy
Genes
Immune System
Epithelial Cells
Mothers
Gene Expression
Pregnancy
Mortality

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Rogers, T. J., Christenson, J. L., Greene, L. I., O'Neill, K. I., Williams, M. M., Gordon, M. A., ... Richer, J. K. (2019). Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression. Molecular Cancer Research, 17(1), 30-41. https://doi.org/10.1158/1541-7786.MCR-18-0246

Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression. / Rogers, Thomas J.; Christenson, Jessica L.; Greene, Lisa I.; O'Neill, Kathleen I.; Williams, Michelle M.; Gordon, Michael A.; Nemkov, Travis; D'Alessandro, Angelo; Degala, Greg D.; Shin, Jimin; Tan, Aik-Choon; Cittelly, Diana M.; Lambert, James R.; Richer, Jennifer K.

In: Molecular Cancer Research, Vol. 17, No. 1, 01.01.2019, p. 30-41.

Research output: Contribution to journalArticle

Rogers, TJ, Christenson, JL, Greene, LI, O'Neill, KI, Williams, MM, Gordon, MA, Nemkov, T, D'Alessandro, A, Degala, GD, Shin, J, Tan, A-C, Cittelly, DM, Lambert, JR & Richer, JK 2019, 'Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression', Molecular Cancer Research, vol. 17, no. 1, pp. 30-41. https://doi.org/10.1158/1541-7786.MCR-18-0246
Rogers, Thomas J. ; Christenson, Jessica L. ; Greene, Lisa I. ; O'Neill, Kathleen I. ; Williams, Michelle M. ; Gordon, Michael A. ; Nemkov, Travis ; D'Alessandro, Angelo ; Degala, Greg D. ; Shin, Jimin ; Tan, Aik-Choon ; Cittelly, Diana M. ; Lambert, James R. ; Richer, Jennifer K. / Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression. In: Molecular Cancer Research. 2019 ; Vol. 17, No. 1. pp. 30-41.
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abstract = "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{\th}) breast cancer. In normal epithelial cells and ER{\th} 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{\th} 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.",
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