Circular RNA circEGFR overexpression attenuates chemosensitivity and enhances cancer stemness via targeting IGF2BP2/SOX2 in breast cancer cells

Abstract Breast cancer (BC) has a high incidence and mortality rate among women. Doxorubicin (DOX) is one of the standard chemotherapeutic drugs for BC. However, chemoresistance to DOX represents a major therapeutic obstacle, and its underlying mechanisms remain elusive. CircEGFR (hsa_circ_0080222) is significantly upregulated in BC tissues and drives the malignant progression of BC. However, the role of circEGFR in DOX resistance remains unclear. In this study, we found that circEGFR expression was significantly upregulated in DOX-resistant MCF-7 (MCF-7/DOX) cells. CircEGFR overexpression attenuated DOX sensitivity in MCF-7 cells, as evidenced by increased cell viability and enhanced proliferative capacity. Notably, circEGFR also enhanced cancer stem cell (CSC) properties in BC cells. Conversely, circEGFR knockdown reduced chemoresistance and stem-like properties in both MDA-MB-231 and MCF-7/DOX cells. Mechanistically, circEGFR interacted with IGF2BP2 to enhance the stability of the stem cell marker SOX2 mRNA, resulting in elevated SOX2 expression. Rescue experiments demonstrated that silencing IGF2BP2 or SOX2 abrogated circEGFR-mediated chemoresistance and stemness properties in BC cells. In conclusion, our study demonstrates for the first time that circEGFR drives DOX chemoresistance and maintains cancer stemness in BC cells via the IGF2BP2/SOX2 axis. Targeting circEGFR may be considered a promising therapeutic strategy for overcoming chemotherapy resistance in BC.