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 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.
Highlights
Growth differentiation factor 15 (GDF15; referred to as macrophage inhibitory cytokine-1, MIC-1, and nonsteroidal anti-inflammatory drug activated gene1, NAG-1) is a stress-induced inflammatory cytokine [1, 2]
We demonstrate that growth differentiation factor 15 (GDF15) promotes epithelial mesenchymal transition (EMT) and invasiveness of breast cancers through insulin-like growth factor-1 receptor (IGF-1R) signaling and transcription factor FoxM1 upregulation
The molecular subtypes of breast cancers represented in the cohort were consistent with published literature [6, 20], with 68% estrogen receptor (ER)-positive tumors and 13% human epidermal growth factor receptor 2 (HER2)-positive
Summary
Growth differentiation factor 15 (GDF15; referred to as macrophage inhibitory cytokine-1, MIC-1, and nonsteroidal anti-inflammatory drug activated gene, NAG-1) is a stress-induced inflammatory cytokine [1, 2]. GDF15 is expressed abundantly only in the placenta. Stressors, such as inflammation and injury, induce GDF15 expression in epithelial cells, fibroblasts, and macrophages. Many pathologic conditions, including insulin resistance, diabetes, cardiovascular disease, impaired cognitive ability, and malignancies, are associated with elevated levels of circulating GDF15 [3,4,5]. Patients with advanced-stage cancers, including breast, express high levels of GDF15 in tumor tissues and/or sera [6,7,8,9,10].
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