TY - JOUR
T1 - Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression
AU - Rogers, Thomas J.
AU - Christenson, Jessica L.
AU - Greene, Lisa I.
AU - O'Neill, Kathleen I.
AU - Williams, Michelle M.
AU - Gordon, Michael A.
AU - Nemkov, Travis
AU - D'Alessandro, Angelo
AU - Degala, Greg D.
AU - Shin, Jimin
AU - Tan, Aik Choon
AU - Cittelly, Diana M.
AU - Lambert, James R.
AU - Richer, Jennifer K.
N1 - Funding Information:
Colorado-Anschutz Medical Campus (Aurora, CO). We thank Lei Zhao, University of Iowa (Iowa City, IA) for technical expertise and Nicole Spoelstra and Jill Slansky, PhD, for valuable editing. The study was supported by DOD BCRP Breakthrough Level 2 Award W81XWH-15-1-0039 (to J.K. Richer); CU Cancer Center's Women's Event/The Salah Foundation (to J.K. Richer); F99 CA212230-01 NCI Pre to Postdoctoral Fellow Transition Award (to T.J. Rogers); NRSA T32 CA190216-01A1 (to J.L. Christenson); NRSA F31 CA203486-01A1 (to L.I. Greene).
Publisher Copyright:
2018 American Association for Cancer Research.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85057484278&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-18-0246
DO - 10.1158/1541-7786.MCR-18-0246
M3 - Article
C2 - 30213797
AN - SCOPUS:85057484278
SN - 1541-7786
VL - 17
SP - 30
EP - 41
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 1
ER -