[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-378411-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-378411-en":131},{"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","cholesterol-biogenesis-is-a-pten-dependent-actionable-node-for-the-treatment-of-endocrine-therapy-refractory-cancers","Cholesterol biogenesis is a PTEN-dependent actionable node for the treatment of endocrine therapy-refractory cancers","","PTEN and PIK3CA mutations are common PI3K-pathway alterations across prostate, breast, colorectal, and endometrial cancers, with p110β becoming prominent after PTEN loss. This study uses bioinformatic analysis of microarray datasets with aberrant PI3K activation to show that SQLE, a rate-limiting enzyme in cholesterol biogenesis, is significantly upregulated in p110β-hyperactivated or PTEN-deficient mouse prostate tumors. SQLE and cholesterol biosynthesis enzymes correlate with PI3K activation and decrease after PTEN re-expression, accompanied by reduced cholesteryl esters and free cholesterol. PTEN-null prostate and breast cancer cells are more sensitive to pharmacological cholesterol-pathway intervention, and combined cholesterol inhibition plus androgen receptor coinhibition enhances antihormone-therapy sensitivity in PTEN-null castration-resistant prostate cancer and PTEN-suppressed luminal-A breast cancer cells, supporting a potential hormone-resistance treatment strategy.",{"@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/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/cholesterol-biogenesis-is-a-pten-dependent-actionable-node-for-the-treatment-of-endocrine-therapy-refractory-cancers/378411/",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/cholesterol-biogenesis-is-a-pten-dependent-actionable-node-for-the-treatment-of-endocrine-therapy-refractory-cancers/378411.png","ImageObject",300,407,{"name":42,"@type":43},"Elsa","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-27","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",11,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What is the central role of PTEN loss in PI3K pathway activity in this study?","Question",{"text":63,"@type":64},"PTEN loss leads to overactivation of the PI3K pathway, making cancer cells primarily dependent on the p110β isoform and altering downstream metabolic signaling relevant to tumor growth and therapy response.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"Which enzyme in cholesterol biogenesis is identified as rate-limiting and upregulated under PTEN loss?",{"text":68,"@type":64},"SQLE (squalene epoxidase) is identified as the rate-limiting enzyme of cholesterol biogenesis and is significantly upregulated in p110β-hyperactivated or PTEN-deficient mouse prostate tumors.",{"name":70,"@type":61,"acceptedAnswer":71},"How does PTEN re-expression affect cholesterol-related markers and therapeutic sensitivity?",{"text":72,"@type":64},"PTEN re-expression decreases SQLE protein levels and reduces cholesteryl esters and free cholesterol. PTEN-null prostate and breast cancer cells also show greater sensitivity to pharmacological intervention targeting the cholesterol pathway, and combined strategies with androgen receptor inhibition further enhance antihormone therapy sensitivity.","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},378411,1790330814,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"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":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":124,"doc_module":4,"doc_module_name":25,"category_name":125,"show_sort_weight":124,"slug":126},10,"Lifestyle","lifestyle",{"id":128,"doc_module":4,"doc_module_name":25,"category_name":129,"show_sort_weight":97,"slug":130},19,"General","general",{"code":4,"msg":82,"data":132},{"doc_id":79,"user_id":133,"nickname":42,"user_avatar":134,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":55,"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},137455077381,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","DOI: 10. 1111/cas.15960  \nOR I G I NAL ART I C L E  \nCholesterol biogenesis is a PTEN-dependent actionable node for the treatment of endocrine therapy-refractory cancers  \nIrmak Kaysudu1 | Taha Bugra Gungul1 | Sena Atici1 | Sevval Yilmaz1 | Engin Bayram2 | Gozde Guven3 | Nihal Terzi Cizmecioglu3 | Ozgur Sahin4 | Gurkan Yesiloz5 |  \nBerat Zeki Haznedaroglu2 | Onur Cizmecioglu1,6   \n1Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey  \n2Institute of Environmental Sciences, Bogazici University, Istanbul, Turkey 3 Department of Biological Sciences, Middle East Technical University, Ankara, Turkey  \n4Department of Biochemistry and Molecular Biology, Hollings Cancer Center, MUSC, Charleston, South Carolina, USA  \n5Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey  \n6Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey  \nCorrespondence  \nOnur Cizmecioglu, Department of Molecular Biology and Genetics, Faculty of Science, SB-310, Bilkent University, Ankara 06800, Turkey. [Email:](Email: onur.cizmecioglu@bilkent.edu.tr)[ onur.cizmecioglu@bilkent.edu.tr](Email: onur.cizmecioglu@bilkent.edu.tr)  \nFunding information  \nTürkiye Bilimsel ve Teknolojik Araştırma Kurumu, Grant/Award Number: 118Z976  \nAbstract  \nPTEN and PIK3CA mutations are the most prevalent PI3K pathway alterations in prostate, breast, colorectal, and endometrial cancers. p110β becomes the prominent PI3Kisoform upon PTEN loss. In this study, we aimed to understand the molecular mechanisms of PI3K dependence in the absence of PTEN. Using online bioinformatical tools, we examined two publicly available microarray datasets with aberrant PI3K activation. We found that the rate-limiting enzyme of cholesterol biogenesis, SQLE, was significantly upregulated in p110β-hyperactivated or PTEN-deficient mouse prostate tumors. Concomitantly, the expression of cholesterol biosynthesis pathway enzymes was directly correlated with PI3K activation status in microarray datasets and diminished upon PTEN re-expression in PTEN-null prostate cancer cells. Particularly, PTEN re-expression decreased SQLE protein levels in PTEN-deficient prostate cancer cells. We performed targeted metabolomics and detected reduced levels of cholesteryl esters as well as free cholesterol upon PTEN re-expression. Notably, PTEN-null prostate and breast cancer cell lines were more sensitive to pharmacological intervention with the cholesterol pathway than PTEN-replete cancer cells. Since steroid hormones use sterols as structural precursors, we studied whether cholesterol biosynthesis may be a metabolic vulnerability that enhances antihormone therapy in PTEN-null castration-resistant prostate cancer cells. Coinhibition of cholesterol biosynthesis and the androgen receptor enhanced their sensitivity. Moreover, PTEN suppression in endocrine therapy-resistant luminal-A breast cancer cells leads to an increase in SQLE expression and a corresponding sensitization to the inhibition of cholesterol synthesis. According to our data, targeting cholesterol biosynthesis in combination with the  \nAbbreviations: CDI, coefficient of drug interaction; DAVID database, Database for Annotation, Visualization and Integrated Discovery; DMSO, dimethylsulfoxide; ENTPD5, ectonucleoside triphosphate diphosphohydrolase 5; GEO, Gene Expression Omnibus; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; KEGG, Kyoto Encyclopedia of Genes and Genomes; KM plotter, Kaplan–Meier plotter; PH domain, Pleckstrin homology domain; PI, phosphatidylinositol; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol trisphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; SQLE, squalene epoxidase; SREBP1C, sterol-regulatory element-binding protein 1C.  \nIrmak Kaysudu, Taha Bugra Gungul, and Sena Atici contributed equally to this work.  \nThis is an open access article under the terms of ","cbCaid8wXxQrplxI","https://ap.wps.com/l/cbCaid8wXxQrplxI","pdf",8869287,"English","# Introduction\n## PI3K/PTEN signaling and tumor dependence\n# Abstract","[{\"question\":\"What is the central role of PTEN loss in PI3K pathway activity in this study?\",\"answer\":\"PTEN loss leads to overactivation of the PI3K pathway, making cancer cells primarily dependent on the p110β isoform and altering downstream metabolic signaling relevant to tumor growth and therapy response.\"},{\"question\":\"Which enzyme in cholesterol biogenesis is identified as rate-limiting and upregulated under PTEN loss?\",\"answer\":\"SQLE (squalene epoxidase) is identified as the rate-limiting enzyme of cholesterol biogenesis and is significantly upregulated in p110β-hyperactivated or PTEN-deficient mouse prostate tumors.\"},{\"question\":\"How does PTEN re-expression affect cholesterol-related markers and therapeutic sensitivity?\",\"answer\":\"PTEN re-expression decreases SQLE protein levels and reduces cholesteryl esters and free cholesterol. PTEN-null prostate and breast cancer cells also show greater sensitivity to pharmacological intervention targeting the cholesterol pathway, and combined strategies with androgen receptor inhibition further enhance antihormone therapy sensitivity.\"}]","Cholesterol biogenesis is a PTEN-dependent actionable node for the treatment of endocrine therapy-refractory cancers | PDF",1790229929,28]