Growth differentiation factor 15 mediates epithelial mesenchymal transition and invasion of breast cancers through IGF-1R-FoxM1 signaling
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Bridgette F. Peake1,6,*, Siobhan M. Eze2,*, Lily Yang5,6, Robert C. Castellino3,6 and Rita Nahta1,2,4,6
1Molecular & Systems Pharmacology PhD Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA, USA
2Department of Pharmacology, School of Medicine, Emory University, Atlanta, GA, USA
3Department of Pediatrics, School of Medicine, Emory University, Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA, USA
4Department of Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA, USA
5Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
6Winship Cancer Institute, Emory University, Atlanta, GA, USA
*These authors have contributed equally to this work
Rita Nahta, email: RNAHTA@EMORY.EDU
Keywords: breast cancer, signaling, invasion
Received: April 26, 2017 Accepted: September 15, 2017 Published: October 10, 2017
Expression of the inflammatory cytokine growth differentiation factor 15 (GDF15) is significantly elevated in many tumor types in association with epithelial mesenchymal transition (EMT), drug resistance, and progressive disease. However, few studies have examined GDF15 expression, signaling, or function in breast cancer. In the current study, we demonstrate that GDF15 is associated with high tumor grade, ER-negativity, and HER2 overexpression in patients with breast cancer. Stable overexpression of GDF15 upregulates expression of mesenchymal markers and transcription factors, including FoxM1, and increases cellular invasion. GDF15 stable clones and breast cancer cells stimulated with recombinant human GDF15 (rhGDF15) demonstrate activation of insulin-like growth factor-1 receptor (IGF-1R), EMT, and invasion. Pharmacologic inhibition of IGF-1R reduces GDF15-mediated EMT and invasion in stable clones, and FoxM1 knockdown rescues invasion and EMT in GDF15 stable clones and rhGDF15-stimulated cells. These data suggest that IGF-1R-FoxM1 signaling is a potential mechanism through which GDF15 drives EMT and invasion of breast cancers. Further, GDF15 knockdown significantly inhibits invasion of HER2-overexpressing and triple-negative breast cancer cells, supporting further preclinical investigation of GDF15-targeted therapies.
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