Mechanistic insight into sex differences in lung cancer induced by cRaf

Mechanistic insight into sex differences in lung cancer induced by cRaf | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Mechanistic insight into sex differences in lung cancer induced by cRaf Shen Zhong, Jürgen Borlak This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2599586/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Women are at greater risk of developing lung cancer (LC); yet the underlying causes are unknown. To gain insight into sex difference in LC, we investigated tumor growth in a cRaf transgenic disease model. Overexpression of the cRaf kinase induced an extraordinary 8-fold increase in tumor growth among females, and nearly 70% of the 112 differentially expressed genes (DEGs) were female specific. We identified oncogenes, oncomirs, tumor suppressors, cell cycle regulators and MAPK/EGFR signaling molecules, which prompted sex-based differences in LC, and we report a regulatory gene-network, which protected males from accelerated tumor growth. Strikingly, 41% of DEGs are targets of hormone receptors, and the majority (85%) are estrogen receptor (ER) dependent. We confirmed the role of ER in a large cohort of LC patients and validated 40% of DEGs induced by cRaf in clinical tumor samples. Together, we report a molecular circuitry that prompted gender disparities in tumor growth, and propose the development of molecular targeted therapies by jointly blocking ER, CDK1 and arginase 2 activity in LC. Health sciences/Oncology/Cancer/Lung cancer/Non-small-cell lung cancer Health sciences/Medical research/Preclinical research Lung cancer cRaf kinase gender MAPK/EGFR signaling hormone receptors transcription factor-miRNA gene regulatory network clinical validation Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTableS12ListofCDK1targetgenesidentifiedinfemaleandmaleclinicalsamplesoftheTCGAdatabase.xlsx Supplementary Table S12 SupplementaryTableS3.DifferentiallyexpressedgenesandmiRNAsinlungtumorsofcRaftransgenicmice.xlsx Supplementary Table S3 SupplementaryTableS4.EnrichedGOtermsforDEGsbasedonannotationsbytheMetascapeandgeneXplainsoftware.xlsx Supplementary Table S4 SupplementaryTableS5.Listofimmunecellmarkergenes.WeretrievedtheinformationfromtheCellMarkerdatabaseandpublishedliterature.xlsx Supplementary Table S5 SupplementaryTableS6.ListofoncogenesoncomirsandtumorsuppressorsregulatedinlungtumorsofcRaftransgenicmice.xlsx Supplementary Table S6 SupplementaryTableS7.ListofDEGsandDEMswithpromoterbindingsitesfortheandrogenandestrogenreceptor.xlsx Supplementary Table S7 SupplementaryTableS8EnrichedtranscriptionfactorbindingsitesinpromotersofDEGs.xlsx Supplementary Table S8 SupplementaryTableS9ListofDEGsandDEMsidentifiedinclinicalsamplesfromtheTCGAdatabase.xlsx Supplementary Table S9 SupplementaryTableS10TumorassociatedmacrophagegenesregulatedinclinicalsamplesoftheTCGAdatabase.xlsx Supplementary Table S10 SupplementaryTableS11SexdisparitiesinDEGsandDEMsidentifiedinclinicalsamplesoftheTCGAdatabase.xlsx Supplementary Table S11 SupplementaryTableS12.pdf Supplementary Tables S1-S2 SupplementaryTableS13EstrogenreceptortargetgenesidentifiedinfemaleandmaleinclinicalsamplesoftheTCGAdatabase.xlsx Supplementary Table S13 Supplementaryfigures.docx Supplementary Figures S1-S5 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2599586","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":178327130,"identity":"c79336ed-3925-49fb-9655-ff8c09e4afa4","order_by":0,"name":"Shen Zhong","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shen","middleName":"","lastName":"Zhong","suffix":""},{"id":178327131,"identity":"b0bb6529-5d8a-496c-bd8d-17a6a5d7ba4e","order_by":1,"name":"Jürgen 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