Targeting estrogen-regulated system xc − promotes ferroptosis and endocrine sensitivity of ER+ breast cancer
Abstract 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. In...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07354-0 |
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| author | Jiawei Cao Tong Zhou Tao Wu Rixu Lin Ju Huang Dejin Shi Jiawei Yu Yinrui Ren Changrui Qian Licai He Guang Wu Zhixiong Dong Shaofei Yuan Haihua Gu |
| author_facet | Jiawei Cao Tong Zhou Tao Wu Rixu Lin Ju Huang Dejin Shi Jiawei Yu Yinrui Ren Changrui Qian Licai He Guang Wu Zhixiong Dong Shaofei Yuan Haihua Gu |
| author_sort | Jiawei Cao |
| collection | DOAJ |
| description | Abstract 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 xc −, 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 xc − 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. |
| format | Article |
| id | doaj-art-3b4b131e2a674cbd8e31eeed03074fb2 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-3b4b131e2a674cbd8e31eeed03074fb22025-01-26T12:54:47ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111410.1038/s41419-025-07354-0Targeting estrogen-regulated system xc − promotes ferroptosis and endocrine sensitivity of ER+ breast cancerJiawei Cao0Tong Zhou1Tao Wu2Rixu Lin3Ju Huang4Dejin Shi5Jiawei Yu6Yinrui Ren7Changrui Qian8Licai He9Guang Wu10Zhixiong Dong11Shaofei Yuan12Haihua Gu13Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical UniversityWenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical UniversityWenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical UniversityDepartment of Pathology, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical UniversityWenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical UniversityWenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical UniversityWenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversityWenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical UniversityWenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical UniversityWenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical UniversityDepartment of Medical Oncology, Rui’an People’s Hospital, The Third Affiliated Hospital of Wenzhou Medical UniversityWenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical UniversityAbstract 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 xc −, 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 xc − 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.https://doi.org/10.1038/s41419-025-07354-0 |
| spellingShingle | Jiawei Cao Tong Zhou Tao Wu Rixu Lin Ju Huang Dejin Shi Jiawei Yu Yinrui Ren Changrui Qian Licai He Guang Wu Zhixiong Dong Shaofei Yuan Haihua Gu Targeting estrogen-regulated system xc − promotes ferroptosis and endocrine sensitivity of ER+ breast cancer Cell Death and Disease |
| title | Targeting estrogen-regulated system xc − promotes ferroptosis and endocrine sensitivity of ER+ breast cancer |
| title_full | Targeting estrogen-regulated system xc − promotes ferroptosis and endocrine sensitivity of ER+ breast cancer |
| title_fullStr | Targeting estrogen-regulated system xc − promotes ferroptosis and endocrine sensitivity of ER+ breast cancer |
| title_full_unstemmed | Targeting estrogen-regulated system xc − promotes ferroptosis and endocrine sensitivity of ER+ breast cancer |
| title_short | Targeting estrogen-regulated system xc − promotes ferroptosis and endocrine sensitivity of ER+ breast cancer |
| title_sort | targeting estrogen regulated system xc promotes ferroptosis and endocrine sensitivity of er breast cancer |
| url | https://doi.org/10.1038/s41419-025-07354-0 |
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