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.
Methods and results
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.
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Breast cancer stem cells
Cancer stem cells
Forkhead box M1
Growth Differentiation Factor-15
Human epidermal growth factor receptor
Octamer-binding transcription factor 4
Sex determining region Y-box 2
Transforming growth factor-β
Triple negative breast cancer
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This work was supported by the Intramural Funding of AIIMS, Jodhpur under Grant Number (AIIMS/RES/2019/3056) and Department of Biotechnology, Ministry of Science and Technology under Grant Number (DBT/2018/AIIMS-J/994).
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Modi, A., Purohit, P., Roy, D. et al. FOXM1 mediates GDF-15 dependent stemness and intrinsic drug resistance in breast cancer. Mol Biol Rep 49, 2877–2888 (2022). https://doi.org/10.1007/s11033-021-07102-5
- Breast cancer
- Drug resistance
- Triple negative breast cancer