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This study integrates single-cell RNA sequencing and TCGA transcriptomic profiles, applying hdWGCNA to link molecular modules to clinical traits. Chloride intracellular channel 6 (CLIC6) is identified as a key hub gene: CLIC6 overexpression increases radioresistance, while CLIC6 knockdown restores radiosensitivity. Theaflavin binds CLIC6 with high affinity and enhances radiosensitivity in a CLIC6-dependent manner.",{"@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":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/targeting-clic6-with-theaflavin-enhances-radiotherapy-sensitivity-in-erher2-breast-cancer-research-findings/448570/",{"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/targeting-clic6-with-theaflavin-enhances-radiotherapy-sensitivity-in-erher2-breast-cancer-research-findings/448570.png","ImageObject",300,407,{"name":92,"@type":93},"Connor ","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is this study focused on ER+/HER2− breast cancer radiotherapy resistance?","Question",{"text":112,"@type":113},"ER+/HER2− tumors commonly exhibit intrinsic radioresistance, which limits radiotherapy benefits. The study aims to uncover molecular determinants that drive this resistance and enable improved treatment outcomes.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was CLIC6 identified as a key gene?",{"text":117,"@type":113},"The study integrated ER+/HER2− single-cell RNA sequencing data before and after radiotherapy with TCGA transcriptomic profiles. hdWGCNA highlighted a luminal A-like module, in which CLIC6 emerged as a hub gene linked to clinical traits.",{"name":119,"@type":110,"acceptedAnswer":120},"What role does theaflavin play in relation to CLIC6?",{"text":121,"@type":113},"Molecular docking showed theaflavin specifically binds CLIC6 with high affinity. Functional assays demonstrated that theaflavin enhances radiosensitivity in wild-type and CLIC6-overexpressing cells, but not when CLIC6 is knocked down or when ER is negative.","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},448570,1790981183,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"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},687207022233,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Targeting CLIC6 with theaflavin enhances radiotherapy sensitivity in ER+/HER2 − breast cancer  \nMengying Suo1, Lin Liu2, Tiantian She3, Chong Chen1  \n1School of Medicine, Nankai University, Tianjin, China; 2Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, China; 3School of Medical Technology, Tianjin Medical University, Tianjin, China  \nContributions: (I) Conception and design: M Suo; (II) Administrative support: T She; (III) Provision of study materials or patients: L Liu, C Chen; (IV) Collection and assembly of data: M Suo; (V) Data analysis and interpretation: M Suo; (VI) Manuscript writing: All authors; (VII) Final approval of  \nmanuscript: All authors.  \nCorrespondence to: Chong Chen, PhD. School of Medicine, Nankai University, No. 94 Weijin Road, Nankai District, Tianjin 300071, China. [Email: Chongchen@tmu.edu.cn](Email: Chongchen@tmu.edu.cn); Tiantian She, PhD. School of Medical Technology, Tianjin Medical University, No. 22 Qixiangtai Road, Heping  \nDistrict, Tianjin 300070, China. Email: [tiantianshe@tmu.edu.cn](tiantianshe@tmu.edu.cn).  \nBackground: Radiotherapy is a cornerstone of breast cancer treatment; however, estrogen receptorpositive (ER+)/human epidermal growth factor receptor 2-negative (HER2 − ) tumors frequently exhibit intrinsic radioresistance. Understanding the molecular mechanisms underlying this resistance is crucial for improving therapeutic outcomes. This study aims to identify key molecular determinants of intrinsic radioresistance in ER+/HER2 − breast cancer and to explore potential radiosensitization strategies targeting  \nthese determinants.  \nMethods: We integrated single-cell RNA sequencing (scRNA-seq) data from ER+/HER2 − breast tumors before and after radiotherapy with transcriptomic profiles from The Cancer Genome Atlas (TCGA) . A high-dimensional weighted gene co-expression network analysis (hdWGCNA) was employed to identify gene modules associated with clinical traits. Functional assays were conducted in ER+ breast cancer cells with chloride intracellular channel 6 (CLIC6) overexpression or knockdown. A molecular docking analysis revealed that theaflavin specifically interacts with CLIC6. Further, clonogenic assays and Cell Counting Kit-8 (CCK-8) proliferation assays were performed to validate the biological effects of theaflavin and CLIC6  \nfollowing radiotherapy.  \nResults: The hdWGCNA identified a luminal A-like gene module correlated with progesterone receptor (PR) positivity and low Ki67 expression, within which CLIC6 emerged as a key hub gene. Elevated CLIC6 expression enhanced radioresistance, whereas CLIC6 knockdown increased radiosensitivity. Molecular docking confirmed that theaflavin binds to CLIC6 with high affinity (binding energy −8.8 kcal/mol) .  \nTheaflavin treatment significantly enhanced radiosensitivity in wild-type and CLIC6-overexpressing cells  \nbut had no effect in CLIC6-knockdown or ER-negative (ER −) cells.  \nConclusions: This study identified CLIC6 as a novel gene associated with radioresistance in ER+/HER2 − breast cancer and showed that theaflavin functions as a natural radiosensitizer in a CLIC6-dependent manner, consistent with its high-affinity interaction with CLIC6. Targeting CLIC6 may provide a promising  \nstrategy to enhance radiotherapy efficacy in this common breast cancer subtype.  \nKeywords: Breast cancer; chloride intracellular channel 6 (CLIC6); radiotherapy sensitivity; theaflavin; tumor cell  \nSubmitted Nov 08, 2025. Accepted for publication Dec 16, 2025. Published online Dec 29, 2025.  \ndoi: 10.21037/tcr-2025-aw-2466  \nView this article at: [https://dx.doi.org/10.21037/tcr-2025-aw-2466](https://dx.doi.org/10.21037/tcr-2025-aw-2466)  \n© AME Publishing Company. Transl Cancer Res 2025;14(12):9002-9014 | [https://dx.doi.org/10.21037/tcr-2025-aw-2466](https://dx.doi.org/10.21037/tcr-2025-aw-2466)  \nTranslational Cancer Research, Vol 14, No 12 December 2025 9003  \nIntroduction  \nBreast cancer is the most comm","cbCaivFUF0g2PU9q","https://ap.wps.com/l/cbCaivFUF0g2PU9q","pdf",4335714,13,"English","# Introduction\n## Breast cancer subtype and radioresistance\n## Rationale for radiosensitizers\n## CLIC6 and theaflavin\n# Methods\n## Integrated scRNA-seq and TCGA analysis (hdWGCNA)\n## CLIC6 perturbation in ER+ breast cancer cells\n## Molecular docking\n## Clonogenic and proliferation assays\n# Results\n## hdWGCNA module discovery and CLIC6 hub gene\n## Effects of CLIC6 on radiosensitivity\n## Theaflavin binding and radiosensitization specificity\n# Conclusions","[{\"question\":\"Why is this study focused on ER+/HER2− breast cancer radiotherapy resistance?\",\"answer\":\"ER+/HER2− tumors commonly exhibit intrinsic radioresistance, which limits radiotherapy benefits. The study aims to uncover molecular determinants that drive this resistance and enable improved treatment outcomes.\"},{\"question\":\"How was CLIC6 identified as a key gene?\",\"answer\":\"The study integrated ER+/HER2− single-cell RNA sequencing data before and after radiotherapy with TCGA transcriptomic profiles. hdWGCNA highlighted a luminal A-like module, in which CLIC6 emerged as a hub gene linked to clinical traits.\"},{\"question\":\"What role does theaflavin play in relation to CLIC6?\",\"answer\":\"Molecular docking showed theaflavin specifically binds CLIC6 with high affinity. Functional assays demonstrated that theaflavin enhances radiosensitivity in wild-type and CLIC6-overexpressing cells, but not when CLIC6 is knocked down or when ER is negative.\"}]","Targeting CLIC6 with theaflavin enhances radiotherapy sensitivity in ER+/HER2 − breast cancer - Research findings | PDF",1790727904,33]