[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-333058-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-333058-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","wnt4-regulates-cellular-metabolism-via-intracellular-activity-at-the-mitochondria-in-breast-and-gynecologic-cancers","WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers","","Wnt ligand WNT4 is essential for female reproductive tissue development, and WNT4 dysregulation is linked to breast cancer (invasive lobular carcinoma) and gynecologic cancers. WNT4 signaling in these settings differs from canonical Wnt yet remains insufficiently understood. The study examines intracellular WNT4 functions independent of Wnt secretion and links convergent dysregulation mechanisms to altered cancer metabolism. It shows WNT4 localized to cytosol and mitochondria, driving metabolic reprogramming through fatty acid and amino acid pathways, with AMPK activation associated with a relevant ER-binding-site polymorphism.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/wnt4-regulates-cellular-metabolism-via-intracellular-activity-at-the-mitochondria-in-breast-and-gynecologic-cancers/333058/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/wnt4-regulates-cellular-metabolism-via-intracellular-activity-at-the-mitochondria-in-breast-and-gynecologic-cancers/333058.png","ImageObject",300,407,{"name":42,"@type":43},"Jiven","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-04","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",9,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"How does WNT4 regulate cellular metabolism in these cancers?","Question",{"text":63,"@type":64},"The study shows that intracellular (non-secretory) WNT4 activity localizes to the cytosol and mitochondria and mediates metabolic reprogramming through fatty acid and amino acid metabolism pathways.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What is the relationship between WNT4 and estrogen receptor signaling in invasive lobular carcinoma?",{"text":68,"@type":64},"In invasive lobular carcinoma, WNT4 is co-opted by estrogen receptor alpha via genomic binding in WNT4 intron 1, linking estrogen-driven regulation to WNT4-mediated metabolic effects.",{"name":70,"@type":61,"acceptedAnswer":71},"What role does the ER-binding-site polymorphism rs3820282 play in gynecologic cancer metabolism?",{"text":72,"@type":64},"The rs3820282 polymorphism at the ER binding site alters WNT4 regulation; cell lines carrying the variant genotype are WNT4 dependent with active WNT4 metabolic signaling, and tumors show metabolic remodeling with increased AMPK activation.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},333058,1790012883,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,111,115,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":108,"show_sort_weight":109,"slug":110},7,"Healthcare",40,"healthcare",{"id":112,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":113,"slug":114},8,30,"research-report",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":112,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145,"preview_page_count":4},1099513958607,"https://ap-avatar.wpscdn.com/avatar/100002390cf8733938c?x-image-process=image/resize,m_fixed,w_180,h_180&k=1778829742770036399","RESEARCH ARTICLE  [https://doi.org/10.1158/2767-9764.CRC-23-0275](https://doi.org/10.1158/2767-9764.CRC-23-0275)   \nWNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers  \nJoseph L. Sottnik1 , Madeleine T. Shackleford1 , Sydney K. Robinson1 , Fabian R. Villagomez2 , Shaymaa Bahnassy3 , Steffi Oesterreich4 , Junxiao Hu5 , Zeynep Madak-Erdogan6 , Rebecca B. Riggins3 , Bradley R. Corr7 , Linda S. Cook8 , Lindsey S. Treviño9 ,  \nBenjamin G. Bitler2 , and Matthew J. Sikora1  \nOPEN  \nACCESS  \nCheck for updates  \nABSTRACT  \nWnt ligand WNT4 is critical in female reproductive tissue development, with WNT􀀂 dysregulation linked to related pathologies including breast cancer (invasive lobular carcinoma, ILC) and gynecologic cancers. WNT4 signaling in these contexts is distinct from canonical Wnt signaling yet inadequately understood. We previously identified atypical intracellular activity of WNT4 (independent of Wnt secretion) regulating mitochondrial function, and herein examine intracellular functions of WNT4 . We further examine how convergent mechanisms of WNT􀀂 dysregulation impact cancer metabolism. In ILC, WNT􀀂 is co-opted by estrogen receptor α (ER) via genomic binding in WNT􀀂 intron 1, while in gynecologic cancers, a common genetic polymorphism (rs3820282) at this ER binding site alters WNT􀀂 regulation. Using proximity biotinylation (BioID), we show canonical Wnt ligand WNT3A is trafficked for secretion, but WNT4 is localized to the cytosol and mitochondria. We identified DHRS2, mTOR, and STAT1 as putative WNT4 cytosolic/mitochondrial signaling partners. Whole metabolite profiling, and integrated transcriptomic data, support that WNT4 mediates metabolic reprogramming via fatty acid and amino  \nacid metabolism. Furthermore, ovarian cancer cell lines with rs3820282 variant genotype are WNT4 dependent and have active WNT4 metabolic signaling. In protein array analyses of a cohort of 103 human gynecologic tumors enriched for patient diversity, germline rs3820282 genotype is associated with metabolic remodeling. Variant genotype tumors show increased AMPK activation and downstream signaling, with the highest AMPK signaling activity in variant genotype tumors from non-White patients. Taken  \ntogether, atypical intracellular WNT4 signaling, in part via genetic dysregulation, regulates the distinct metabolic phenotypes of ILC and gynecologic cancers.  \nSignificance: WNT4 regulates breast and gynecologic cancer metabolism via a previously unappreciated intracellular signaling mechanism at the mitochondria, with WNT4 mediating metabolic remodeling. Understanding WNT􀀂 dysregulation by estrogen and genetic polymorphism offers new opportunities for defining tumor biology, precision therapeutics, and personalized cancer risk assessment.  \nIntroduction  \nThe Wnt ligand WNT4, considered a “problem child” among Wnts (1, 2), is broadly critical for organogenesis and development. Complete loss-of-function  \n1 Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 2 Division of Reproductive Sciences, Department of Obstetricsand Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 3 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia. 4 Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania. 5 Biostatistics and Bioinformatics Shared Resource, University of Colorado Cancer Center, Aurora, Colorado. 6 Department of Food Science and Human Nutrition, Cancer Center at Illinois, Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Champaign, Illinois. 7 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 8 Department of Epidemiology, University of Colorado School of Public Health, Aurora, Colorado.  \nis lethal in uter","cbCaioJPR7W4t6gh","https://ap.wps.com/l/cbCaioJPR7W4t6gh","pdf",15967666,18,"English","# Abstract\n## Background and rationale\n## Intracellular WNT4 mechanisms\n## Metabolic reprogramming findings\n## Clinical relevance and polymorphism associations\n# Introduction\n## Role of WNT4 in development and disease","[{\"question\":\"How does WNT4 regulate cellular metabolism in these cancers?\",\"answer\":\"The study shows that intracellular (non-secretory) WNT4 activity localizes to the cytosol and mitochondria and mediates metabolic reprogramming through fatty acid and amino acid metabolism pathways.\"},{\"question\":\"What is the relationship between WNT4 and estrogen receptor signaling in invasive lobular carcinoma?\",\"answer\":\"In invasive lobular carcinoma, WNT4 is co-opted by estrogen receptor alpha via genomic binding in WNT4 intron 1, linking estrogen-driven regulation to WNT4-mediated metabolic effects.\"},{\"question\":\"What role does the ER-binding-site polymorphism rs3820282 play in gynecologic cancer metabolism?\",\"answer\":\"The rs3820282 polymorphism at the ER binding site alters WNT4 regulation; cell lines carrying the variant genotype are WNT4 dependent with active WNT4 metabolic signaling, and tumors show metabolic remodeling with increased AMPK activation.\"}]","WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers | PDF",1790000654,45]