Activation of PERK/eIF2α/ATF4 signaling inhibits ERα expression in breast cancer
Approximately 70–80% of breast cancers rely on estrogen receptor alpha (ERα) for growth. The unfolded protein response (UPR), a cellular response to endoplasmic reticulum stress (ERS), is an important process crucial for oncogenic transformation. The effect of ERS on ERα expression and signaling rem...
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| Format: | Article |
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Elsevier
2025-07-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000442 |
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| author | Yuanli Wu Gang Wang Ruixue Yang Duanfang Zhou Qingjuan Chen Qiuya Wu Bo Chen Lie Yuan Na Qu Hongmei Wang Moustapha Hassan Ying Zhao Mingpu Liu Zhengze Shen Weiying Zhou |
| author_facet | Yuanli Wu Gang Wang Ruixue Yang Duanfang Zhou Qingjuan Chen Qiuya Wu Bo Chen Lie Yuan Na Qu Hongmei Wang Moustapha Hassan Ying Zhao Mingpu Liu Zhengze Shen Weiying Zhou |
| author_sort | Yuanli Wu |
| collection | DOAJ |
| description | Approximately 70–80% of breast cancers rely on estrogen receptor alpha (ERα) for growth. The unfolded protein response (UPR), a cellular response to endoplasmic reticulum stress (ERS), is an important process crucial for oncogenic transformation. The effect of ERS on ERα expression and signaling remains incompletely elucidated. Here, we focused on the regulatory mechanisms of ERS on ERα expression in ER-positive breast cancer (ER+ BC). Our results demonstrate that ERα protein and mRNA levels in ER+ BC cells are considerably reduced by the ERS inducers thapsigargin (TG) and brefeldin A (BFA) via the PERK/eIF2α/ATF4 signaling pathway. ChIP-qPCR and luciferase reporter gene analysis revealed that ERS induction facilitated ATF4 binding to the ESR1 (the gene encoding ERα) promoter region, thereby suppressing ESR1 promoter activity and inhibiting ERα expression. Furthermore, selective activation of PERK signaling or ATF4 overexpression attenuated ERα expression and tumor cell growth both in vitro and in vivo. In conclusion, our results demonstrate that ERS suppresses ERα expression transcriptionally via the PERK/eIF2α/ATF4 signaling. Our study provides insights into the treatment of ER+ BC by targeting ERα signaling through selective activation of the PERK branch of the UPR. |
| format | Article |
| id | doaj-art-acd234a67df34251bdbdcb18319ea252 |
| institution | OA Journals |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-acd234a67df34251bdbdcb18319ea2522025-08-20T01:54:21ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-07-016510116510.1016/j.neo.2025.101165Activation of PERK/eIF2α/ATF4 signaling inhibits ERα expression in breast cancerYuanli Wu0Gang Wang1Ruixue Yang2Duanfang Zhou3Qingjuan Chen4Qiuya Wu5Bo Chen6Lie Yuan7Na Qu8Hongmei Wang9Moustapha Hassan10Ying Zhao11Mingpu Liu12Zhengze Shen13Weiying Zhou14Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Drug Metabolism, Chongqing Medical University, Chongqing, 400016, PR China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, PR ChinaDepartment of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Drug Metabolism, Chongqing Medical University, Chongqing, 400016, PR China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, PR ChinaDepartment of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Drug Metabolism, Chongqing Medical University, Chongqing, 400016, PR China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, PR ChinaDepartment of Pharmacy, Women and Children’s Hospital of Chongqing Medical University/Chongqing Health Center for Women and Children, Chongqing, 401147, PR ChinaDepartment of Oncology, 3201 Hospital of Xi'an Jiaotong University Health Science Center, Hanzhong, 723000, Shaanxi, PR ChinaDepartment of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Drug Metabolism, Chongqing Medical University, Chongqing, 400016, PR China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, PR ChinaDepartment of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Drug Metabolism, Chongqing Medical University, Chongqing, 400016, PR China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, PR ChinaDepartment of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Drug Metabolism, Chongqing Medical University, Chongqing, 400016, PR China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, PR ChinaDepartment of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Drug Metabolism, Chongqing Medical University, Chongqing, 400016, PR China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, PR ChinaDepartment of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Drug Metabolism, Chongqing Medical University, Chongqing, 400016, PR China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, PR China; Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR ChinaExperimental Cancer Medicine, Division of Biomolecular and Cellular Medicine (BCM), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, 14186, SwedenExperimental Cancer Medicine, Division of Biomolecular and Cellular Medicine (BCM), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, 14186, SwedenDepartment of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Drug Metabolism, Chongqing Medical University, Chongqing, 400016, PR China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, PR ChinaDepartment of Pharmacy, Yongchuan Hospital of Chongqing Medical University, Chongqing, 402160, PR China; Corresponding authors.Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Drug Metabolism, Chongqing Medical University, Chongqing, 400016, PR China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, PR China; Corresponding authors.Approximately 70–80% of breast cancers rely on estrogen receptor alpha (ERα) for growth. The unfolded protein response (UPR), a cellular response to endoplasmic reticulum stress (ERS), is an important process crucial for oncogenic transformation. The effect of ERS on ERα expression and signaling remains incompletely elucidated. Here, we focused on the regulatory mechanisms of ERS on ERα expression in ER-positive breast cancer (ER+ BC). Our results demonstrate that ERα protein and mRNA levels in ER+ BC cells are considerably reduced by the ERS inducers thapsigargin (TG) and brefeldin A (BFA) via the PERK/eIF2α/ATF4 signaling pathway. ChIP-qPCR and luciferase reporter gene analysis revealed that ERS induction facilitated ATF4 binding to the ESR1 (the gene encoding ERα) promoter region, thereby suppressing ESR1 promoter activity and inhibiting ERα expression. Furthermore, selective activation of PERK signaling or ATF4 overexpression attenuated ERα expression and tumor cell growth both in vitro and in vivo. In conclusion, our results demonstrate that ERS suppresses ERα expression transcriptionally via the PERK/eIF2α/ATF4 signaling. Our study provides insights into the treatment of ER+ BC by targeting ERα signaling through selective activation of the PERK branch of the UPR.http://www.sciencedirect.com/science/article/pii/S1476558625000442Breast cancerESR1ERαEndoplasmic reticulum stressUnfolded protein responseATF4 |
| spellingShingle | Yuanli Wu Gang Wang Ruixue Yang Duanfang Zhou Qingjuan Chen Qiuya Wu Bo Chen Lie Yuan Na Qu Hongmei Wang Moustapha Hassan Ying Zhao Mingpu Liu Zhengze Shen Weiying Zhou Activation of PERK/eIF2α/ATF4 signaling inhibits ERα expression in breast cancer Neoplasia: An International Journal for Oncology Research Breast cancer ESR1 ERα Endoplasmic reticulum stress Unfolded protein response ATF4 |
| title | Activation of PERK/eIF2α/ATF4 signaling inhibits ERα expression in breast cancer |
| title_full | Activation of PERK/eIF2α/ATF4 signaling inhibits ERα expression in breast cancer |
| title_fullStr | Activation of PERK/eIF2α/ATF4 signaling inhibits ERα expression in breast cancer |
| title_full_unstemmed | Activation of PERK/eIF2α/ATF4 signaling inhibits ERα expression in breast cancer |
| title_short | Activation of PERK/eIF2α/ATF4 signaling inhibits ERα expression in breast cancer |
| title_sort | activation of perk eif2α atf4 signaling inhibits erα expression in breast cancer |
| topic | Breast cancer ESR1 ERα Endoplasmic reticulum stress Unfolded protein response ATF4 |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000442 |
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