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FOXM1 mediates GDF-15 dependent stemness and intrinsic drug resistance in breast cancer

Authors :
Anupama Modi
Purvi Purohit
Dipayan Roy
Jeewan Ram Vishnoi
Puneet Pareek
Poonam Elhence
Priyanka Singh
Shailja Sharma
Praveen Sharma
Sanjeev Misra
Source :
Molecular Biology Reports. 49:2877-2888
Publication Year :
2022
Publisher :
Springer Science and Business Media LLC, 2022.

Abstract

Stemness, a key component of breast cancer (BC) heterogeneity, is responsible for chemoresistance. Growth differentiation factor-15 (GDF-15) induces drug resistance and stemness in BC cells. In this study, the expressions and interactions of GDF-15, FOXM1, and stemness (OCT4 and SOX2), and drug resistance (ABCC5) markers were evaluated in BC.40 diagnosed BC patients and 40 healthy controls were included in this study. Serum GDF-15 was significantly raised (p 0.001) in BC patients. Expressions of GDF-15, OCT4, SOX2, and FOXM1 in BC tissue and cell lines (MCF-7 and MDA-MB-231) were determined by RT-PCR, while phosphorylated AKT (p-AKT) was analyzed by Western blot. Not only were the fold change expressions higher in cancer tissue as compared to surrounding control tissue, but a higher expression was observed for all the genes along with p-AKT in MDA-MB-231 cells compared to MCF-7. Tissue GDF-15 was significantly associated with ABCC5 (p 0.001), OCT4 (p = 0.002), SOX2 (p 0.001), and FOXM1 (p 0.001). To further analyze the signaling pathway involved in stemness and drug resistance in BC, GDF-15 knockdown was performed, which reduced the expression of p-AKT, FOXM1, OCT4 and SOX2, and ABCC5, whereas recombinant GDF-15 treatment reversed the same. In silico analyses in UALCAN revealed a similar picture for these genes to that of BC tissue expression.GDF-15 promotes stemness and intrinsic drug resistance in BC, possibly mediated by the p-AKT/FOXM1 axis.

Details

ISSN :
15734978 and 03014851
Volume :
49
Database :
OpenAIRE
Journal :
Molecular Biology Reports
Accession number :
edsair.doi.dedup.....454b91e7e64044eac285d12ab8d9b799
Full Text :
https://doi.org/10.1007/s11033-021-07102-5