Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression
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+) 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2019
- Source ID
- 10.1158/1541-7786.mcr-18-0246
Entities
People
- Aik-choon Tan
- Angelo D'Alessandro
- Diana M Cittelly
- Greg D. Degala
- James R. Lambert
- Jennifer K Richer
- Jessica L Christenson
- Jimin Shin
- Kathleen I. O’neill
- Lisa I. Greene
- Michael A. Gordon
- Michelle M. Williams
- Thomas J. Rogers
- Travis Nemkov
Organizations
- Israel National Road Safety Authority
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense
- University of Colorado