Targeting estrogen-regulated system x_c^- promotes ferroptosis and endocrine sensitivity of ER+ breast cancer

Estrogen receptor positive (ER+) breast cancer accounts for approximately 70% of cases. Endocrine therapies targeting estrogen are the first line therapies for ER+ breast cancer. However, resistance to these therapies occurs in about half of patients, leading to decreased survival rates. Inducing ferroptosis is a promising therapeutic strategy for cancer treatment for refractory and malignant cancers including triple-negative breast cancer. Nevertheless, ER+ breast cancer is relatively resistant to ferroptosis inducers. Here, we uncovered that ERα suppressed ferroptosis in ER+ breast cancer. Silencing ERα triggered ferroptosis, which was attenuated by ferroptosis inhibitor Ferrostatin-1, and was enhanced by ferroptosis inducer Erastin. Mechanistically, ERα transcriptionally upregulated the expression of SLC7A11 and SLC3A2, two subunits of the system x_c^-, which is one key inhibitory regulator of ferroptosis. Overexpression of the exogenous SLC7A11 and SLC3A2 was able to mitigate ferroptosis induced by ERα inhibition. Moreover, SLC7A11 and SLC3A2 levels were elevated in endocrine-resistant breast cancer cells and tumors. Importantly, the system x_c^- inhibitor Sorafenib or Imidazole ketone erastin effectively inhibited the growth of tamoxifen-resistant breast cells in vitro and in vivo. In conclusion, our data reveal that targeting estrogen-regulated SLC7A11 and SLC3A2 enhances ferroptosis in ER+ breast cancer, offering a novel therapeutic option for patients with ER+ breast cancer, particularly those with endocrine resistance.