From Pathway to Patient: Molecular Dysregulation as Basis for Minimal Sequential Intervention Strategy in Basal-Like Breast Cancer

From Pathway to Patient: Molecular Dysregulation as Basis for Minimal Sequential Intervention Strategy in Basal-Like Breast Cancer | 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 Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article From Pathway to Patient: Molecular Dysregulation as Basis for Minimal Sequential Intervention Strategy in Basal-Like Breast Cancer Aamer Bhatti This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8942485/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Aggressive breast cancer subtypes like triple-negative and basal-like tumors exhibit widespread dysregulation across multiple signaling pathways, requiring multi-pathway therapeutic strategies. Boolean network models can integrate large-scale genomic data with mechanistic pathway knowledge, but face scalability challenges. We present BBCN118, a modular Boolean network framework comprising 118 genes decomposed across fifteen pathways including apoptosis, cell cycle, MAPK, PI3K AKTmTOR, JAK–STAT, hormone signaling, Wnt, and NFKB. Using TCGA mRNA profiles from basal-like breast cancer patients, we initialize patient-specific pathway states. Our central theoretical contribution is a Lyapunov-based decomposition theorem demonstrating that global network dynamics can be approximated by independent pathway-level analysis under mild coupling conditions, enabling scalable intervention design. The BBCN118 pipeline identifies minimal node perturbations driving each pathway toward biologically curated target states. Across deceased basal-like breast cancer patients, sequential pathway interventions achieved less than 20 percent mismatch reduction toward healthy attractors in most cases. Kernel frequency analysis revealed key intervention hubs (CDKN1A, CDKN2A, JAK2) consistent with known regulatory roles. BBCN118 provides a transparent, computationally efficient framework integrating patient omics with mechanistic modeling, advancing interpretable multi-pathway analysis for precision oncology. Biological sciences/Cancer Biological sciences/Computational biology and bioinformatics Full Text Additional Declarations No competing interests reported. Supplementary Files Supplementary.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 06 May, 2026 Reviews received at journal 07 Apr, 2026 Reviews received at journal 19 Mar, 2026 Reviewers agreed at journal 17 Mar, 2026 Reviewers agreed at journal 17 Mar, 2026 Reviewers agreed at journal 05 Mar, 2026 Reviewers invited by journal 02 Mar, 2026 Editor invited by journal 02 Mar, 2026 Editor assigned by journal 26 Feb, 2026 Submission checks completed at journal 25 Feb, 2026 First submitted to journal 25 Feb, 2026 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board 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-8942485","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":599506385,"identity":"66e25086-9b93-4572-9714-65c23255c84d","order_by":0,"name":"Aamer Bhatti","email":"data:image/png;base64,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","orcid":"","institution":"King Fahd University of Petroleum and Minerals","correspondingAuthor":true,"prefix":"","firstName":"Aamer","middleName":"","lastName":"Bhatti","suffix":""}],"badges":[],"createdAt":"2026-02-23 03:23:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8942485/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8942485/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103961623,"identity":"3f380075-ced8-4566-89ce-4b3343112759","added_by":"auto","created_at":"2026-03-05 04:56:16","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":498180,"visible":true,"origin":"","legend":"","description":"","filename":"ScientificReports2026bbcn118submittedonFeb23.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8942485/v1_covered_ef54521e-af7e-4ec0-90e5-21bd5487956e.pdf"},{"id":103961606,"identity":"eb25e6e2-1363-4b30-b99a-517449325da4","added_by":"auto","created_at":"2026-03-05 04:56:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":117475,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8942485/v1/6405a3bea08d72db66c5237a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"From Pathway to Patient: Molecular Dysregulation as Basis for Minimal Sequential Intervention Strategy in Basal-Like Breast Cancer","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8942485/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8942485/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAggressive breast cancer subtypes like triple-negative and basal-like tumors exhibit widespread dysregulation across multiple signaling pathways, requiring multi-pathway therapeutic strategies. Boolean network models can integrate large-scale genomic data with mechanistic pathway knowledge, but face scalability challenges. We present BBCN118, a modular Boolean network framework comprising 118 genes decomposed across fifteen pathways including apoptosis, cell cycle, MAPK, PI3K AKTmTOR, JAK–STAT, hormone signaling, Wnt, and NFKB. Using TCGA mRNA profiles from basal-like breast cancer patients, we initialize patient-specific pathway states. Our central theoretical contribution is a Lyapunov-based decomposition theorem demonstrating that global network dynamics can be approximated by independent pathway-level analysis under mild coupling conditions, enabling scalable intervention design. The BBCN118 pipeline identifies minimal node perturbations driving each pathway toward biologically curated target states. Across deceased basal-like breast cancer patients, sequential pathway interventions achieved less than 20 percent mismatch reduction toward healthy attractors in most cases. Kernel frequency analysis revealed key intervention hubs (CDKN1A, CDKN2A, JAK2) consistent with known regulatory roles. 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