Abstract
PURPOSE: Breast cancer is a significant global health issue, with resistance to doxorubicin (DOX) posing a major challenge to effective treatment. SUMOylation, a post-translational modification process, is linked to cancer progression and therapy resistance. PIAS4, a SUMO E3 ligase involved in maintaining genome stability and stress response, may play a role in these mechanisms. However, its function in breast cancer progression and DOX resistance remains uncertain. This study investigates the potential role of PIAS4 in mediating DOX resistance in breast cancer. METHODS AND RESULTS: Naked mole-rats (NMRs) are cancer-resistant rodents with improved genome maintenance, yet the role of SUMOylation in this trait remains unclear. SUMOylation machinery gene expression levels are investigated using qPCR in NMR tissue in comparison with carcinogenic breast cancer (MCF-7) cell line. Functional studies are performed in MCF-7 cells overexpressing PIAS4 to demonstrate effects on proliferation, invasion, drug sensitivity, and protein expression in the presence and absence of DOX treatment. While most SUMOylation genes were expressed at low levels in NMR intestinal tissues, PIAS4 showed higher expression compared to MCF-7 cells. PIAS4 overexpression in MCF-7 cells significantly decreases colony formation, invasiveness, and resistance to DOX. Western blot analysis showed downregulated Bcl-2 protein levels after DOX treatment, indicating a potential role in apoptosis evasion. CONCLUSION: PIAS4 expression level plays a role in breast cancer cell survival, invasiveness, and chemoresistance, partly by altering anti-apoptotic pathways. These findings position PIAS4 as a potential biomarker and therapeutic target for overcoming resistance to anthracycline-based therapies in breast cancer.