Growth differentiation factor 15 mediates epithelial mesenchymal transition and invasion of breast cancers through IGF-1R-FoxM1 signaling

• Type of Material: Article
• Authors: Bridgette F. Peake, Emory University; Siobhan M. Eze, Emory University; Lily Yang, Emory University; Robert Craig Castellino, Emory University; Rita Nahta, Emory University
• Language: English
• Date: 2017-11-07
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Peake et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.21765
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 8
• Issue: 55
• Start Page: 94393
• End Page: 94406
• Grant/Funding Information: RN acknowledges funding from Winship Cancer Institute through the Glenn Breast Cancer Research Scholars Program and Owenby Research Award, and from the Emory University Research Committee.; BFP is supported by diversity training supplement R01CA157754-05S1.
• Keywords: ACTIVATION; EMT; Cell Biology; CONTRIBUTES; GDF15; CELLS; MACROPHAGE INHIBITORY CYTOKINE-1; signaling; Oncology; Science & Technology; breast cancer; SUPERFAMILY; RESISTANCE; invasion; Life Sciences & Biomedicine; RECEPTOR; METASTASIS
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

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 insulinlike growth factor-1 receptor (IGF-1R), EMT, and invasion. Ph armacologic 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.