Targeting ESR1 restores SQSTM1-dependent autophagy and sensitizes ER-positive breast cancer to oxidative and radiation stress.

Estrogen receptor-positive (ER⁺) breast cancer is commonly treated with hormone therapy; however, these tumors frequently develop drug resistance and exhibit poor responses to radiotherapy. To investigate the molecular basis of therapy resistance, we explored the role of estrogen receptor alpha (ESR1) in modulating sensitivity to oxidative and radiation stress. Through integrative analysis of publicly available datasets, we identified ESR1 as a key molecular marker associated not only with breast cancer classification but also with radiosensitivity. In ER⁺ breast cancer cell lines, higher endogenous ESR1 expression correlated with increased resistance to ionizing radiation. Functional studies using ESR1 overexpression and knockdown models revealed that depletion of ESR1 sensitized cells to radiation-induced DNA damage, impaired DNA repair efficiency, and reduced clonogenic survival. Notably, we found that the ESR1-SQSTM1 (p62) interaction impairs autophagic flux, contributing to treatment resistance. Mechanistically, ESR1 translocates to the cytoplasm and binds to SQSTM1, thereby disrupting autophagosome maturation. Furthermore, estradiol enhances ESR1 phosphorylation and its affinity for SQSTM1, reinforcing this inhibitory effect on autophagy and promoting resistance to radiation. Our findings uncover a previously unrecognized ESR1-SQSTM1 axis that governs autophagy and redox response in ER⁺ breast cancer. Targeting this pathway may restore sensitivity to radiotherapy and offer a new therapeutic strategy. Assessment of ESR1 expression and autophagy activity may serve as predictive biomarkers for treatment response in ER⁺ breast cancer patients.