Growth Differentiation Factor 15 Mediates Epithelial Mesenchymal Transition and Invasion of Breast Cancers Through IGF-1R-FoxM1 Signaling

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Dec 8

PMID 29212236

Citations 29

Authors

Bridgette F Peake

Siobhan M Eze

Lily Yang

Robert C Castellino

Rita Nahta

Affiliations

Soon will be listed here.

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.

Citing Articles

Macrophages as a Source and Target of GDF-15.

Silva-Bermudez L, Kluter H, Kzhyshkowska J Int J Mol Sci. 2024; 25(13).

PMID: 39000420 PMC: 11242731. DOI: 10.3390/ijms25137313.

GALNT14 in association with GDF-15 promotes stemness and drug resistance through β-catenin signalling pathway in breast cancer.

Gadwal A, Purohit P, Khokhar M, Vishnoi J, Pareek P, Choudhary R Mol Biol Rep. 2024; 51(1):691.

PMID: 38796671 DOI: 10.1007/s11033-024-09645-9.

Aberrant expression of bone morphogenetic proteins in the disease progression and metastasis of breast cancer.

Liu M, Sui L, Fang Z, Jiang W, Ye L Front Oncol. 2023; 13:1166955.

PMID: 37333824 PMC: 10272747. DOI: 10.3389/fonc.2023.1166955.

The Role of Polo-Like Kinase 1 in Regulating the Forkhead Box Family Transcription Factors.

Moore X, Gheghiani L, Fu Z Cells. 2023; 12(9).

PMID: 37174744 PMC: 10177174. DOI: 10.3390/cells12091344.

Bone morphogenetic proteins, activins, and growth and differentiation factors in tumor immunology and immunotherapy resistance.

Ganjoo S, Puebla-Osorio N, Nanez S, Hsu E, Voss T, Barsoumian H Front Immunol. 2022; 13:1033642.

PMID: 36353620 PMC: 9638036. DOI: 10.3389/fimmu.2022.1033642.

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