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Dysregulated ETHE1 is linked to ethylmalonic encephalopathy, but its role in TNBC has been unclear. ETHE1 overexpression or knockdown was examined in stable cell models in vitro and in vivo, with mass spectrometry to define molecular mechanisms. ETHE1 did not alter proliferation or xenograft growth but enhanced migration, invasion, and lung metastasis. This tumor-promoting effect depended on ETHE1-driven eIF2α phosphorylation via eIF2α–GCN2 interaction and subsequent ATF4 upregulation, partially reversed by ISRIB or ATF4 knockdown, suggesting ETHE1-targeted therapy.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/ethe1-accelerates-triple-negative-breast-cancer-metastasis-by-activating-gcn2eif2atf4-signaling/384114/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/ethe1-accelerates-triple-negative-breast-cancer-metastasis-by-activating-gcn2eif2atf4-signaling/384114.png","ImageObject",300,407,{"name":92,"@type":93},"eBook King","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-28","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does ETHE1 affect TNBC progression in vitro and in vivo?","Question",{"text":112,"@type":113},"ETHE1 did not change TNBC cell proliferation or xenograft tumor growth, but it promoted TNBC cell migration and invasion in vitro and increased lung metastasis in vivo.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What signaling pathway connects ETHE1 to enhanced TNBC metastasis?",{"text":117,"@type":113},"ETHE1 interacts with eIF2α and enhances its phosphorylation by promoting the interaction between eIF2α and GCN2; phosphorylated eIF2α then upregulates ATF4, which activates migration and metastasis-related genes.",{"name":119,"@type":110,"acceptedAnswer":120},"Does ETHE1’s effect depend on its enzymatic activity?",{"text":121,"@type":113},"The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},384114,1790629779,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36},962088006270,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","Article  \nETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2􀀋/ATF4 Signaling  \nShao-Ying Yang 1,2,3,†, Li Liao 1,2,3,†, Shu-Yuan Hu 1, Ling Deng 1, Lisa Andriani 4, Tai-Mei Zhang 1, Yin-Ling Zhang 2, Xiao-Yan Ma 4, Fang-Lin Zhang 2, Ying-Ying Liu 4,* and Da-Qiang Li 1,2,3,4,5,6, *  \nCitation: Yang, S.-Y.; Liao, L.; Hu, S.-Y.; Deng, L.; Andriani, L.; Zhang, T.-M.; Zhang, Y.-L.; Ma, X.-Y.; Zhang, F.-L.; Liu, Y.-Y.; et al. ETHE1  \nAccelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2􀀋/ATF4 Signaling. Int. J. Mol. Sci. 2023, 24, 14566. [https://](https://)[ ](https://)[doi.org/10.3390/ijms241914566](doi.org/10.3390/ijms241914566)  \nAcademic Editors: Masa-Aki Shibataand Sasagu Kurozumi  \nReceived: 12 July 2023  \nRevised: 10 September 2023  \nAccepted: 12 September 2023  \nPublished: 26 September 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; [19211510017@fudan.edu.cn](19211510017@fudan.edu.cn) (S.-Y.Y.); [16211220054@fudan.edu.cn](16211220054@fudan.edu.cn) (L.L.); [18111510026@fudan.edu.cn](18111510026@fudan.edu.cn) (S.-Y.H.); [20111510058@fudan.edu.cn](20111510058@fudan.edu.cn) (L.D.); [17111510026@fudan.edu.cn](17111510026@fudan.edu.cn) (T.-M.Z.)  \n2 Cancer Institute, Shanghai Medical College, Fudan University, Shanghai 200032, China; [23111230017@fudan.edu.cn](23111230017@fudan.edu.cn) (Y.-L.Z.); [zhangfanglin555@sina.com](zhangfanglin555@sina.com) (F.-L.Z.)  \n3 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China  \n4 Department of Breast Surgery, Shanghai Medical College, Fudan University, Shanghai 200032, China; [20111230078@fudan.edu.cn](20111230078@fudan.edu.cn) (L.A.); [xyma20@fudan.edu.cn](xyma20@fudan.edu.cn) (X.-Y.M.)  \n5 Shanghai Key Laboratory of Breast Cancer, Shanghai Medical College, Fudan University, Shanghai 200032, China  \n6 Shanghai Key Laboratory of Radiation Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China  \n* Correspondence: [181111230025@fudan.edu.cn](181111230025@fudan.edu.cn) (Y.-Y.L.); [daqiangli1974@fudan.edu.cn](daqiangli1974@fudan.edu.cn) (D.-Q.L.)† These authors contributed equally to the work.  \nAbstract: Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer; however, effective treatment strategies for TNBC are lacking. Therefore, it is important to explore the mechanism of TNBC metastasis and identify its therapeutic targets. Dysregulation of ETHE1 leads to ethylmalonic encephalopathy in humans; however, the role of ETHE1 in TNBC remains elusive. Stable cell lines with ETHE1 overexpression or knockdown were constructed to explore the biological functions of ETHE1 during TNBC progression in vitro and in vivo. Mass spectrometry was used to analyze the molecular mechanism through which ETHE1 functions in TNBC progression. ETHE1 had no impact on TNBC cell proliferation and xenograft tumor growth but promoted TNBC cell migration and invasion in vitro and lung metastasis in vivo. The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity. Mechanistic investigations revealed that ETHE1 interacted with eIF2􀀋 and enhanced its phosphorylation by promoting the interaction between eIF2􀀋 and GCN2 . Phosphorylated eIF2􀀋 in turn upregulated the expression of ATF4, a transcriptional activator of genes involved in cell migration and tumor metastasis. Notably, inhibition of eIF2􀀋 phosphorylation through ISRIB or ATF4 knockdown partially abolished the tumor-promoting effect of ETHE1 overexpression. ETHE1 h","cbCaid9OkurQCVEb","https://ap.wps.com/l/cbCaid9OkurQCVEb","pdf",3854486,16,"English","# Introduction\n# Abstract\n# Keywords","[{\"question\":\"How does ETHE1 affect TNBC progression in vitro and in vivo?\",\"answer\":\"ETHE1 did not change TNBC cell proliferation or xenograft tumor growth, but it promoted TNBC cell migration and invasion in vitro and increased lung metastasis in vivo.\"},{\"question\":\"What signaling pathway connects ETHE1 to enhanced TNBC metastasis?\",\"answer\":\"ETHE1 interacts with eIF2α and enhances its phosphorylation by promoting the interaction between eIF2α and GCN2; phosphorylated eIF2α then upregulates ATF4, which activates migration and metastasis-related genes.\"},{\"question\":\"Does ETHE1’s effect depend on its enzymatic activity?\",\"answer\":\"The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity.\"}]","ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling | PDF",1790261270]