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By mapping ER translation mechanisms, this work identifies cap-independent, mTOR-insensitive ER synthesis driven by 5’ UTR elements and shows rapid eIF4A inhibition reduces ER and short-lived ER-regulated proteins. Combining eIF4A inhibition with fulvestrant induces synergistic, durable ER suppression and tumor growth control across ligand-independent models, supported by clinical zotatifin findings in ER+ metastatic patients.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/eif4a-controls-translation-of-estrogen-receptor-alpha-and-is-a-therapeutic-target-in-advanced-breast-cancer/333380/",{"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/eif4a-controls-translation-of-estrogen-receptor-alpha-and-is-a-therapeutic-target-in-advanced-breast-cancer/333380.png","ImageObject",300,407,{"name":92,"@type":93},"Aurora","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-13","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is estrogen receptor alpha (ER) important in human breast cancer?","Question",{"text":112,"@type":113},"ER is a ligand-activated transcription factor required for mammary development, and 70–75% of breast tumors retain ER dependence for growth and division.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What causes resistance to hormonal therapies targeting ER?",{"text":117,"@type":113},"Resistance is nearly universal in advanced settings, with most patients developing resistance through genetic alterations that promote ligand-independent ER activation or activation of ER target gene programs.",{"name":119,"@type":110,"acceptedAnswer":120},"How does eIF4A inhibition affect ER expression and tumor growth?",{"text":121,"@type":113},"eIF4A inhibition rapidly reduces ER expression and short-lived ER targets such as cyclin D1, leading to suppression of growth across multiple ligand-independent breast cancer models and enhanced effects when combined with fulvestrant.","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},333380,1790012821,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"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":145,"preview_page_count":4},4810365810221,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","bioRxiv preprint doi: [https://doi.org/10.1101/2024.05.08.593195](https://doi.org/10.1101/2024.05.08.593195); this version posted May 11, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY-ND 4.0 International license.  \neIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer  \nJacob A. Boyer 1,2,3, Malvika Sharma2 , Madeline A. Dorso4, Nicholas Mai5, Corina Amor 1,6, Jason  \nM. Reiter2, Ram Kannan6 , Sunyana Gadal2, Jianing Xu2, Matthew Miele7, Zhuoning Li7, Xiaoping Chen8, Qing Chang8, Fresia Pareja9, Stephan Worland 10, Douglas Warner10, Sam Sperry10, Gary  \nG. Chiang10, Peggy A.Thompson 10, Guangli Yang11 Ouathek Ouerfelli 11, Elisa de Stanchina8, HansGuido Wendel6, Ezra Y. Rosen5, Sarat Chandarlapaty4,5,12,13* and Neal Rosen2,13*  \n1. Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, USA  \n2. Program in Molecular Pharmacology, Department of Medicine, Memorial SloanKettering Cancer Center (MSKCC), New York, NY, USA.  \n3. Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA  \n4. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.  \n5. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.  \n6. Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.  \n7. Microchemistry and Proteomics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA  \n8. Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 11065, USA  \n9. Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.  \n10. Department of Cancer Biology, eFFECTOR Therapeutics, Inc., San Diego, CA, United States.  \n11. The Organic Synthesis Core Facility, MSK, New York, NY, USA.  \n12. Department of Medicine, Weill Cornell Medicine, New York, NY, USA  \n13. Correspondence: [chandarS@mskcc.org](chandarS@mskcc.org), [rosenn@mskcc.org](rosenn@mskcc.org),  \n* Co-senior author  \nbioRxiv preprint doi: [https://doi.org/10.1101/2024.05.08.593195](https://doi.org/10.1101/2024.05.08.593195); this version posted May 11, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY-ND 4.0 International license.  \nAbstract  \nThe majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is capindependent and mTOR inhibitor insensitive, but dependent on 5’ UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short-lived targets of ER such as cyclin D1 and other components of the cyclin D-CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand-independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A i","cbCaioU9iNyGuvYu","https://ap.wps.com/l/cbCaioU9iNyGuvYu","pdf",1979746,34,"English","# Abstract\n## Introduction\n## Background: ER dependency and resistance\n## PI3K/AKT/mTOR signaling and translation control","[{\"question\":\"Why is estrogen receptor alpha (ER) important in human breast cancer?\",\"answer\":\"ER is a ligand-activated transcription factor required for mammary development, and 70–75% of breast tumors retain ER dependence for growth and division.\"},{\"question\":\"What causes resistance to hormonal therapies targeting ER?\",\"answer\":\"Resistance is nearly universal in advanced settings, with most patients developing resistance through genetic alterations that promote ligand-independent ER activation or activation of ER target gene programs.\"},{\"question\":\"How does eIF4A inhibition affect ER expression and tumor growth?\",\"answer\":\"eIF4A inhibition rapidly reduces ER expression and short-lived ER targets such as cyclin D1, leading to suppression of growth across multiple ligand-independent breast cancer models and enhanced effects when combined with fulvestrant.\"}]","eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer | PDF",1790002171,86]