Background: 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.
Conclusions: GDF-15 promotes stemness and intrinsic drug resistance in BC, possibly mediated by the p-AKT/FOXM1 axis.
Keywords: Breast cancer; Drug resistance; FOXM1; GDF-15; Stemness; Triple negative breast cancer.
© 2021. The Author(s), under exclusive licence to Springer Nature B.V.