Abstract
Recent studies have highlighted the potential of ferroptosis in treating breast cancer. However, the efficacy of ferroptosis induction in the most common subtype, estrogen receptor-positive (ER + ) breast cancer, remains inadequately explored. This study unveils that both short-term and long-term treatment with ER-targeted endocrine agents sensitizes ER+ breast cancer cells to ferroptosis inducers, particularly the GPX4 inhibitor, revealing a non-mutational sensitization mechanism. Based on this finding, we introduce a 55-gene signature score (FERscore) tailored to assess ferroptosis susceptibility in breast cancer. Data from cell lines and primary tumors demonstrate significant lower FERscores in ER+ breast cancer compared to other subtypes; however, FERscores dramatically increase in endocrine-resistant ER+ tumor cells and residual tumors post-endocrine therapy. Furthermore, FERscore correlates positively with mesenchymal traits, stemness, immune cell infiltration, and cancer-associated fibroblasts enrichment, while inversely correlating with estrogen responsiveness and DNA repair capacity. Additionally, the FERscore proves effective in predicting therapeutic responses to anti-ER, anti-HER2, poly (ADP-ribose) polymerase inhibitor, and anti-angiogenesis therapies in breast cancer. In summary, ferroptosis induction emerges as a promising avenue in breast cancer therapy. The FERscore offers an innovative tool for identifying patients who may benefit from ferroptosis-inducing therapies, especially those responsive to GPX4 inhibitors.