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

[This corrects the article DOI: 10.18632/oncotarget.21765.].

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

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.

Anti-Tumor Effects of Peptide Therapeutic and Peptide Vaccine Antibody Co-targeting HER-1 and HER-2 in Esophageal Cancer (EC) and HER-1 and IGF-1R in Triple-Negative Breast Cancer (TNBC).

Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC) and triple-negative breast cancer (TNBC). Current FDA-approved drugs have significant problems of toxicity, safety, selectivity, efficacy and development of resistance. In this manuscript, we demonstrate that rationally designed peptide vaccines/mimics are a viable therapeutic strategy for blocking aberrant molecular signaling pathways with high affinity, specificity, potency and safety. Specifically, we postulate that novel combination treatments targeting members of the EGFR family and IGF-1R will yield significant anti-tumor effects in in vitro models of EC and TNBC possibly overcoming mechanisms of resistance. We show that the combination of HER-1 and HER-2 or HER-1 and IGF-1R peptide mimics/vaccine antibodies exhibited enhanced antitumor properties with significant inhibition of tumorigenesis in OE19 EC and MDA-MB-231 TNBC cell lines. Our work elucidates the mechanisms of HER-1/IGF-1R and HER-1/HER-2 signaling in these cancer cell lines, and the promising results support the rationale for dual targeting with HER-1 and HER-2 or IGF-1R as an improved treatment regimen for advanced therapy tailored to difference types of cancer.