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Methods: ER+ NF1-deficient cell and rat models were used with IncuCyte proliferation assays, Western blotting, RNAseq, Seahorse energetics assays, stable isotope labeling, and mass spectrometry. Results: NF1 loss increased proliferation and pathway signaling while constraining oxidative ATP production, promoting glutamine TCA influx, and expanding lipid pools, altering metabolic-to-targeted inhibitor synergy.",{"@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/nf1-deficiency-drives-metabolic-reprogramming-in-er-breast-cancer/333109/",{"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/nf1-deficiency-drives-metabolic-reprogramming-in-er-breast-cancer/333109.png","ImageObject",300,407,{"name":92,"@type":93},"Himbo","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-21",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 is the main objective of the study on NF1 deficiency in ER+ breast cancer?","Question",{"text":112,"@type":113},"To define how NF1 deficiency drives metabolic reprogramming in ER+ breast cancer and to identify targeted pathway and metabolic inhibitor combination therapies for NF1-deficient tumors.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which experimental models and assays were used to study NF1 deficiency effects?",{"text":117,"@type":113},"NF1-deficient ER+ breast cancer models included an NF1-deficient MCF7 cell line and three Nf1-deficient rat models. Cell proliferation, protein levels, transcriptional changes (RNAseq), cellular energetics (Seahorse assays), isotope tracing, and metabolite pools (mass spectrometry) were measured.",{"name":119,"@type":110,"acceptedAnswer":120},"How does NF1 deficiency change metabolism and inhibitor synergy?",{"text":121,"@type":113},"NF1 deficiency increases proliferation and RAS/PI3K/AKT signaling while constraining oxidative ATP production and limiting energetic flexibility. It drives glutamine into TCA intermediates, expands lipid pools (notably triglycerides), and increases synergy between metabolic inhibitors and traditional targeted inhibitors.","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},333109,1790177677,{"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":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,"preview_page_count":4},687197100911,"https://ap-avatar.wpscdn.com/avatar/a000239b6f1da00475?x-image-process=image/resize,m_fixed,w_180,h_180&k=1785132997149421697","Original Article  \nNF1 deficiency drives metabolic reprogramming in ERþ breast cancer  \nRachel (Rae) J. House1, Elizabeth A. Tovar1, Luke N. Redlon 1, Curt J. Essenburg 1, Patrick S. Dischinger1, Abigail E. Ellis 2, Ian Beddows 3, Ryan D. Sheldon2, Evan C. Lien4, Carrie R. Graveel1, 7,  \nMatthew R. Steensma1, 5, 6, *, 7  \nABSTRACT  \nObjective: NF1 is a tumor suppressor gene and its protein product, neurofibromin, is a negative regulator of the RAS pathway. NF1 is one of the top driver mutations in sporadic breast cancer such that 27 % of breast cancers exhibit damaging NF1 alterations. NF1 loss-of-function is a frequent event in the genomic evolution of estrogen receptor (ER)þ breast cancer metastasis and endocrine resistance. Individuals with Neurofibromatosis type 1 (NF) e a disorder caused by germline NF1 mutations e have an increased risk of dying from breast cancer [1e4] . NFrelated breast cancers are associated with decreased overall survival compared to sporadic breast cancer. Despite numerous studies interrogating the role of RAS mutations in tumor metabolism, no study has comprehensively profiled the NF1-deficient breast cancer metabolome to define patterns of energetic and metabolic reprogramming. The goals of this investigation were (1) to define the role of NF1 deficiency in estrogen receptor-positive (ERþ) breast cancer metabolic reprogramming and (2) to identify potential targeted pathway and metabolic inhibitor combination therapies for NF1-deficient ER þ breast cancer.  \nMethods: We employed two ERþ NF1-deficient breast cancer models: (1) an NF1-deficient MCF7 breast cancer cell line to model sporadic breast cancer, and (2) three distinct, Nf1-deficient rat models to model NF-related breast cancer [1] . IncuCyte proliferation analysis was used to measure the effect of NF1 deficiency on cell proliferation and drug response. Protein quantity was assessed by Western Blot analysis. We then used RNAseq to investigate the transcriptional effect of NF1 deficiency on global and metabolism-related transcription. We measured cellular energetics using Agilent Seahorse XF-96 Glyco Stress Test and Mito Stress Test assays. We performed stable isotope labeling and measured [Ue 13C]-glucose and [Ue13C]-glutamine metabolite incorporation and measured total metabolite pools using mass spectrometry. Lastly, we used a Bliss synergy model to investigate NF1-driven changes in targeted and metabolic inhibitor synergy.  \nResults: Our results revealed that NF1 deficiency enhanced cell proliferation, altered neurofibromin expression, and increased RAS and PI3K/AKT pathway signaling while constraining oxidative ATP production and restricting energetic flexibility. Neurofibromin deficiency also increased glutamine influx into TCA intermediates and dramatically increased lipid pools, especially triglycerides (TG) . Lastly, NF1 deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis.  \nConclusions: NF1 deficiency drives metabolic reprogramming in ERþ breast cancer. This reprogramming is characterized by oxidative ATP constraints, glutamine TCA influx, and lipid pool expansion, and these metabolic changes introduce novel metabolic-to-targeted inhibitorsynergies.  \n􀀁 2024 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)) .  \nKeywords NF1; Breast cancer; Metabolic reprogramming; Metabolic inhibition; Neurofibromatosis Type 1  \n1. INTRODUCTION  \nRecent genomic analyses have identified that the tumor suppressor gene neurofibromin 1 (NF1) is a driver of inherited breast cancer, sporadic breast cancer, and endocrine resistance [2e9] . The NF1 gene product, neurofibromin, is a primary human rat sarcoma viral oncogene homolog (RAS) GTPase a","cbCaihDrljsC5VQI","https://ap.wps.com/l/cbCaihDrljsC5VQI","pdf",3690340,14,"English","# Abstract\n## Objective\n## Methods\n## Results\n## Conclusions\n# Introduction\n# List of Abbreviations","[{\"question\":\"What is the main objective of the study on NF1 deficiency in ER+ breast cancer?\",\"answer\":\"To define how NF1 deficiency drives metabolic reprogramming in ER+ breast cancer and to identify targeted pathway and metabolic inhibitor combination therapies for NF1-deficient tumors.\"},{\"question\":\"Which experimental models and assays were used to study NF1 deficiency effects?\",\"answer\":\"NF1-deficient ER+ breast cancer models included an NF1-deficient MCF7 cell line and three Nf1-deficient rat models. Cell proliferation, protein levels, transcriptional changes (RNAseq), cellular energetics (Seahorse assays), isotope tracing, and metabolite pools (mass spectrometry) were measured.\"},{\"question\":\"How does NF1 deficiency change metabolism and inhibitor synergy?\",\"answer\":\"NF1 deficiency increases proliferation and RAS/PI3K/AKT signaling while constraining oxidative ATP production and limiting energetic flexibility. It drives glutamine into TCA intermediates, expands lipid pools (notably triglycerides), and increases synergy between metabolic inhibitors and traditional targeted inhibitors.\"}]","NF1 deficiency drives metabolic reprogramming in ERþ breast cancer | PDF",1790000891,35]