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This study uses an in silico designed GR activity signature to link GR activity with the proliferative capacity of many primary cancer types. In breast cancer, GR activity status governs luminal subtype identity and relates to patient outcomes. Mechanistically, GR interacts with estrogen receptor (ER) to redistribute ER on chromatin, induces ZBTB16, and triggers epigenetic remodeling with loss of histone acetylation near cancer-driving genes. Epigenetic inhibitors reduce viability in ER-positive cells lacking GR activity, suggesting GR-driven growth control and novel therapeutic candidates.",{"@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/luminal-breast-cancer-identity-is-determined-by-loss-of-glucocorticoid-receptor-activity/381917/",{"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/luminal-breast-cancer-identity-is-determined-by-loss-of-glucocorticoid-receptor-activity/381917.png","ImageObject",300,407,{"name":92,"@type":93},"Fans","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-25","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does the glucocorticoid receptor (GR) play in cancer biology according to the study?","Question",{"text":112,"@type":113},"GR functions as a transcription factor involved in cancer biology. The study links GR activity to proliferative capacity across multiple primary cancer types.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does GR activity affect luminal breast cancer subtype identity?",{"text":117,"@type":113},"In breast cancer, GR activity status determines luminal subtype identity and is associated with implications for patient outcomes.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanisms connect GR to estrogen receptor (ER) and epigenetic changes?",{"text":121,"@type":113},"GR engages with ER, redistributing ER on chromatin. GR activation upregulates ZBTB16 and leads to epigenetic remodeling, including loss of histone acetylation near cancer-driving genes.","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},381917,1790367915,{"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":34,"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},5909892330395,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Article  \nLuminal breast cancer identity is determined by loss of glucocorticoid receptor activity  \nStefan Prekovic1, 2,*,†, Theofilos Chalkiadakis2,†, Merel Roest1,†, Daniel Roden3,4, Catrin Lutz5, Karianne Schuurman1 , Mark Opdam5 , Liesbeth Hoekman6 , Nina Abbott1, Tanja Tesselaar1, Maliha Wajahat7, Amy R Dwyer7, Isabel Mayayo-Peralta1, Gabriela Gomez8 , Maarten Altelaar6,9 , Roderick Beijersbergen10, Balzs Gy˝orffy11,12 , Leonie Young13,14, Sabine Linn5, Jos Jonkers5 , Wayne Tilley7,15 , Theresa Hickey7 , Damir Vareslija8,14 , Alexander Swarbrick3,4  &  \nWilbert Zwart1,16,**  \nAbstract  \nGlucocorticoid receptor (GR) is a transcription factor that plays a crucial role in cancer biology. In this study, we utilized an in silicodesigned GR activity signature to demonstrate that GR relates to the proliferative capacity of numerous primary cancer types. In breast cancer, the GR activity status determines luminal subtype identity and has implications for patient outcomes. We reveal that GR engages with estrogen receptor (ER), leading to redistribution of ER on the chromatin. Notably, GR activation leads to upregulation of the ZBTB16 gene, encoding for a transcriptional repressor, which controls growth in ER-positive breast cancer and associates with prognosis in luminal A patients. In relation to ZBTB16’s repressive nature, GR activation leads to epigenetic remodeling and loss of histone acetylation at sites proximal to cancer-driving genes. Based on these findings, epigenetic inhibitors reduce viability of ER-positive breast cancer cells that display absence of GR activity. Our findings provide insights into how GR controls ERpositive breast cancer growth and may have implications for patients’ prognostication and provide novel therapeutic candidates for breast cancer treatment.  \nKeywords breast cancer; glucocorticoids; luminal breast cancer subtypes; nuclear receptors; ZBTB16  \nSubject Categories Biomarkers; Cancer; Chromatin, Transcription & Genomics  \nDOI 10.15252/emmm.202317737 | Received 21 March 2023 | Revised 27 September 2023 | Accepted 4 October 2023 | Published online 30 October 2023 EMBO Mol Med (2023) 15: e17737  \nIntroduction  \nThe glucocorticoid receptor (GR) is a transcription factor that regulates gene expression in response to glucocorticoids (Desmet & De Bosscher, 2017) . Its role in solid cancers is not fully understood, and the consequences of its signaling within cancer cells remain unclear. While systemic glucocorticoid treatment leads to immunosuppression, the implications of GR activity in cancer cells are multifaceted and context dependent. GR can act as both a tumor suppressor and an oncogene, depending on the cancer type or disease stage (Arora et al, 2013; Terwilliger & Abdul-Hay, 2017;  \n1 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands  \n2 Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands  \n3 Cancer Ecosystems Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia  \n4 School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia  \n5 Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands  \n6 Mass Spectrometry/Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands  \n7 Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia  \n8 School of Pharmacy and Biomolecular Sciences, The Royal College of Surgeons University of Medicine and Health Sciences, Dublin, Ireland  \n9 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands  \n10 Division of Molecular Carcinogenesis and Robotics and Screening Centre, Netherlands Cancer Institute, Amsterdam, The Netherlands  \n11 TTK Cancer Biomarker Research Group, Insti","cbCairxPN2z5OgCW","https://ap.wps.com/l/cbCairxPN2z5OgCW","pdf",3719100,17,"English","# Abstract\n# Introduction","[{\"question\":\"What role does the glucocorticoid receptor (GR) play in cancer biology according to the study?\",\"answer\":\"GR functions as a transcription factor involved in cancer biology. The study links GR activity to proliferative capacity across multiple primary cancer types.\"},{\"question\":\"How does GR activity affect luminal breast cancer subtype identity?\",\"answer\":\"In breast cancer, GR activity status determines luminal subtype identity and is associated with implications for patient outcomes.\"},{\"question\":\"What mechanisms connect GR to estrogen receptor (ER) and epigenetic changes?\",\"answer\":\"GR engages with ER, redistributing ER on chromatin. GR activation upregulates ZBTB16 and leads to epigenetic remodeling, including loss of histone acetylation near cancer-driving genes.\"}]","Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity | PDF",1790247786,43]