SOD1-high fibroblasts derived exosomal miR-3960 promotes cisplatin resistance in triple-negative breast cancer by suppressing BRSK2-mediated phosphorylation of PIMREG

Platinum-based neoadjuvant therapy represented by cisplatin is widely employed in treating Triple-Negative Breast Cancer (TNBC), a particularly aggressive subtype of breast cancer. Nevertheless, the emergence of cisplatin resistance presents a formidable challenge to clinical chemotherapy efficacy. Herein, we revealed the critical role of tumor microenvironment (TME) derived exosomal miR-3960 and phosphorylation at the S16 site of PIMREG in activating NF-κB signaling pathway and promoting cisplatin resistance of TNBC. Detailed regulatory mechanisms revealed that SOD1-upregulated fibroblasts secrete miR-3960 and are then transported into TNBC cells via exosomes. Within TNBC cells, miR-3960 targets and inhibits the expression of BRSK2, an AMPK protein kinase family member. Furthermore, we emphasized that BRSK2 contributes to ubiquitination degradation of PIMREG and modulates subsequent activation of the NF-κB signaling pathway by mediating PIMREG phosphorylation at the S16 site, ultimately affects the cisplatin resistance of TNBC. In conclusion, our research demonstrated the crucial role of SOD1high fibroblast, exosomal miR-3960 and S16 site phosphorylated PIMREG in regulating the NF-κB signaling pathway and cisplatin resistance of TNBC. These findings provided significant potential as biomarkers for accurately diagnosing cisplatin-resistant TNBC patients and guiding chemotherapy strategy selection. •SOD1high fibroblasts are associated with a poor prognosis of Triple-Negative Breast Cancer (TNBC).•SOD1high fibroblast-derived exosomal miR-3960 promotes cisplatin resistance in TNBC.•miR-3960 regulates the NF-κB signaling pathway by inhibiting the expression of BRSK2 gene.•BRSK2 promotes ubiquitination degradation of PIMREG by phosphorylating its S16 site.