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Targeting SRC/STAT3 Signaling Impairs Cancer Stem Cell Activity by Downregulation of Hexokinase-2 in Radioresistant Triple-Negative Breast Cancer Cells 认领 引用 被引量：1
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作者 Yu-Hao Huang Yu-Ci Tu +5 位作者 Peng-Ju Chien An-Jie Lee Chia-Liang Lin Shao-Ti Li Yueh-Chun Lee Wen-Wei Chang 《Oncology Research》 SCIE 2026年第5期584-601,共18页
Background:Triple-negative breast cancer(TNBC)is an aggressive subtype with poor prognosis and resistance to conventional therapies,including radiotherapy.Cancer stem cells(CSCs)drive tumor initiation,metastasis,and t... Background:Triple-negative breast cancer(TNBC)is an aggressive subtype with poor prognosis and resistance to conventional therapies,including radiotherapy.Cancer stem cells(CSCs)drive tumor initiation,metastasis,and therapy resistance in TNBC.Identifying pathways sustaining CSCs in radioresistant TNBC is key for targeted therapies.This study examines SRC proto-oncogene(SRC)and the signal transducer and activator of transcription 3(STAT3)activation in radioresistance and CSC maintenance.Methods:A radioresistant MDA-MB-231 TNBC cell line(231RR)was developed and compared to the parental line for CSC activity and self-renewal.Western blotting assessed molecular changes;functional assays followed SRC and STAT3 inhibitor treatment.SRCY530F overexpression and hexokinase-2(HK2)knockdown evaluated roles in CSC activity and signaling.Pathways were analyzed via metabolic assays,The Cancer Genome Atlas(TCGA)breast cancer datasets,and Harmonizome gene sets.Results:231RR cells exhibited enhanced CSC traits and upregulated SRC/STAT3 signaling,with heightened sensitivity to SRC/STAT3 inhibitors.Forced expression of SRCY530F in parental cells boosted STAT3 activation and CSC activity.SRC/STAT3 inhibition reduced HK2 without impairing glycolysis.HK2 knockdown decreased MYC proto-oncogene(c-MYC)and octamer-binding transcription factor-4(OCT4).Finally,the suppression of epidermal growth factor receptor(EGFR)activation by gefitinib resulted in the inhibition of the SRC/STAT3/HK2 axis.TCGA data linked SRC to glycolytic signatures in breast cancer.Conclusions:The EGFR/SRC/STAT3/HK2 axis drives radioresistance and CSC maintenance in TNBC via HK2 upregulation.HK2 promotes stemness mainly through non-metabolic means,not broad metabolic shifts.Targeting this pathway could overcome radioresistance and enhance TNBC outcomes. 展开更多
关键词 Triple-negative breast cancer radioresistance cancer stem cells SRC signal transducer and activator of transcription 3(STAT3) Hexokinase-2(HK2)
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Integrative multi-omic analysis identified ERBB2 mutations and senescence-driven immune suppression as dual therapeutic targets in LAR triple-negative breast cancer 认领 引用
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作者 Yaxin Zhao Han Wang +3 位作者 Ying Wang Yizhou Jiang Xin Hu Zhiming Shao 《Cancer Biology & Medicine》 SCIE CAS CSCD 2026年第3期374-391,共18页
Objective:The luminal androgen receptor(LAR)subtype of triple-negative breast cancer(TNBC)differentiation displays low proliferation yet strong metastatic potential and a poor chemotherapy response.This study aimed to... Objective:The luminal androgen receptor(LAR)subtype of triple-negative breast cancer(TNBC)differentiation displays low proliferation yet strong metastatic potential and a poor chemotherapy response.This study aimed to define the molecular basis of the LAR subtype and identify actionable therapeutic targets.Methods:Comprehensive multi-omic analyses were performed on the FUSCC-TNBC cohort,integrating whole-exome sequencing,RNA sequencing,and functional validation in vitro and in vivo.Somatic mutation profiling,gene set enrichment analysis(GSEA),and weighted gene co-expression network analysis(WGCNA)were used to define genomic and transcriptomic signatures.A machine learning model using the Mime1 package was applied to derive a senescence-associated prognostic signature(LAR-S)and validation in external cohorts.Immune deconvolution was performed to decipher the tumor microenvironment.Functional assays,patient-derived organoids(PDOs),and TS/V mouse models were used to evaluate therapeutic responses to senescence-modulating agent and immunotherapy combinations.Results:The LAR subtype was enriched for PIK3CA,PTEN,and ERBB2 kinase domain mutations.Functional studies confirmed ERBB2 variants(e.g.,V777L and E698_P699delinsA)as oncogenic drivers conferring sensitivity to neratinib.Transcriptomic analyses revealed a dominant cellular senescence program associated with immune suppression.The LAR-S signature stratified survival across cohorts and predicted immunotherapy resistance.Targeting cellular senescence inhibited LAR subtype organoid growth and when combined with anti-PD-1 therapy synergistically suppressed tumor growth in vivo.Conclusions:The LAR subtype harbors two therapeutic vulnerabilities:ERBB2 mutation-driven kinase activation;and senescencemediated immune evasion.The LAR-S signature enables precise patient stratification and supports senescence-targeted and immunotherapy combination strategies as promising approaches for this refractory TNBC subtype. 展开更多
关键词 Triple-negative breast cancer luminal androgen receptor subtype ERBB2 mutation cellular senescence immunotherapy resistance
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Endoplasmic reticulum stress and mitochondrial apoptosis in thiosemicarbazone copper(Ⅱ) complex-triggered triple-negative breast cancer cell death 认领 引用
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作者 GAI Shuangshuang CAI Jixiang +3 位作者 YANG Moya WU Haijuan FENG Shuzhen JIANG Ming 《无机化学学报》 SCIE CAS CSCD 北大核心 2026年第5期1073-1084,共12页
To investigate the antitumor properties of copper(Ⅱ)complexes,a series of Cucomplexes(C1-C3)derived from 6,7-dihydro-5H-quinoline-8-one thiosemicarbazone ligands was designed and synthesized.These complexes exhibited... To investigate the antitumor properties of copper(Ⅱ)complexes,a series of Cucomplexes(C1-C3)derived from 6,7-dihydro-5H-quinoline-8-one thiosemicarbazone ligands was designed and synthesized.These complexes exhibited significantly higher potency in inhibiting tumor cell growth in vitro compared to cisplatin.Among them,C3 had the highest antitumor activity against MDA-MB-231 cells,with a half maximal inhibitory concentration(IC50)value of 1.42μmol·L-1.Moreover,C3 effectively inhibited the growth of 3D multicellular spheres.Mechanistically,it induced significant reactive oxygen species(ROS)generation,initiating a dual-pathway cytotoxic effect.On the one hand,it triggers endoplasmic reticulum stress and inhibits the activity of the related protein,protein disulfide isomerase(PDI).On the other hand,it induces mitochondrial dysfunction.These combined stresses ultimately lead to the apoptosis of MDA-MB-231 cells. 展开更多
关键词 anticancer triple-negative breast cancer Cu(Ⅱ)complex thiosemicarbazone protein disulfide isomerase
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An Exploratory Study on Prognostic Prediction and Interpretability Analysis in Early-stage Triple-negative Breast Cancer Using Pathological Images 认领 引用
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作者 Zixuan Yang Yaping Lyu +4 位作者 Liuliu Quan Shuyue Chen Yuying Sun Jie Ju Peng Yuan 《Biomedical and Environmental Sciences》 SCIE CAS CSCD 2026年第3期310-326,共17页
Objective To develop a prognostic prediction model for early-stage triple-negative breast cancer(TNBC)using H&E-stained pathological images and to investigate its underlying biological interpretability.Methods A d... Objective To develop a prognostic prediction model for early-stage triple-negative breast cancer(TNBC)using H&E-stained pathological images and to investigate its underlying biological interpretability.Methods A deep learning model was trained on 340 WSIs and externally validated using 81 TCGA cases.Image-derived features extracted through convolutional neural networks were integrated with clinicopathological variables.Model performance was assessed using ROC curve analysis,and interpretability was evaluated by correlating image features with mRNA-seq data and characteristics of the immune microenvironment.Results The model achieved AUCs of 0.86 and 0.75 in the training and validation cohorts,respectively.Analysis using HoVer-Net indicated that lymphocyte abundance was associated with recurrence risk.Texture-related features showed significant correlations with immune cell infiltration and prognostic gene expression profiles.Conclusion This study demonstrates that deep learning can enable accurate prognostic prediction in early-stage TNBC,with interpretable image features that reflect the tumor immune microenvironment and gene expression profiles. 展开更多
关键词 Triple-negative breast cancer Prognostic prediction model Deep learning H&E-stained pathological images Model interpretability
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Tumour-Derived sEVs Promote Triple-Negative Breast Cancer Progression Associated with HAVCR2 Upregulation in Macrophages 认领 引用
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作者 Jia Liu Binqian Wang +11 位作者 Yannan Jin Wenquan Chen Ruohan Shi Weijia Wang Xiaojing Zhang Yi Tan Zhongran Man Bo Hu Lisen Zhu Biao Zhang Chongchan Bao Gongsheng Jin 《Oncology Research》 SCIE 2026年第8期401-422,共22页
Backgrounds:Triple-negative breast cancer(TNBC)is the most aggressive breast cancer subtype with a unique tumor microenvironment,and while Programmed cell death protein 1/Programmed cell death ligand 1(PD-1/PD-L1)bloc... Backgrounds:Triple-negative breast cancer(TNBC)is the most aggressive breast cancer subtype with a unique tumor microenvironment,and while Programmed cell death protein 1/Programmed cell death ligand 1(PD-1/PD-L1)blockade represents a standard immunotherapy,most patients develop primary or acquired resistance,with few alternative immunotherapeutic targets currently available.Therefore,we aimed to identify potential immune checkpoint-related molecules involved in TNBC-macrophage crosstalk,clarify the underlying molecular mechanism mediated by small extracellular vesicles(sEVs),and provide a theoretical basis for the future development of novel immunotherapeutic targets against TNBC.Methods:Single-cell RNA-sequencing(scRNA-seq)datasets for various breast cancer subtypes were used.Pseudotime trajectory,cell-cell communication and Tumor Immune Estimation Resource 2.0(TIMER2)analyses were conducted to characterize the tumour microenvironment(TME).Immunochemistry and immunofluorescence were used to confirm the results of the above analyses.Single-nucleus RNA sequencing(snRNA-seq)was conducted on three pairs of TNBC tumour and adjacent normal tissues.The functions of tumour-associated macrophages(TAMs)and sEVs in TNBC metastasis were explored byWestern blotting,flow cytometry and cell-based experiments.Results:A total of nearly 60,000 high-quality single cells were subjected to scRNA-seq analysis,from which seven major cell types were identified.An overall increase in immune cell proportion was observed in TNBC compared with other subtypes,with the immune cell fraction in TNBC tissues being~1.8-fold higher than that in luminal A/HER2+subtypes(p<0.001).Cell-cell communication analysis indicated that TNBC cells mainly interact with macrophages.Interestingly,HAVCR2,an immune checkpoint,is expressed mainly in macrophages in the TNBC TME.HAVCR2 is associated with macrophage pseudotime progression in TNBC,which was validated by immunofluorescence staining.Moreover,analysis of The Cancer Genome Atlas(TCGA)bulk RNA-seq data revealed that HAVCR2 expression is significantly correlated with M2-like macrophage gene signatures and computationally inferred macrophage infiltration levels in TNBC,and this tissue-level transcriptional correlation is associated with poor patient prognosis.Notably,bulk RNA-seq data cannot define discrete cell subsets,and the identification of HAVCR2+M2 macrophage subsets was independently validated by scRNA-seq and snRNA-seq at the single-cell level.Furthermore,treatment with TNBC-derived sEVs is associated with concurrent increases in the expression of HAVCR2 and M2-associated markers(CD163,CD206)in macrophages.These findings reflect a correlative association rather than a demonstrated causal or regulatory relationship between HAVCR2 and M2-associated marker upregulation.Conclusion:sEVs derived from TNBC cells are associated with the upregulation of M2-associated markers and concomitant HAVCR2 upregulation in macrophages,both of which correlate with TNBC progression and metastasis.We propose that HAVCR2 may serve as a candidate prognostic marker associated with M2-like macrophage features in TNBC,and these foundational in vitro findings from Human acute monocytic leukemia cell line(THP-1)macrophages warrant further validation in primary human monocyte-derived macrophages and in vivo TNBC models. 展开更多
关键词 Breast cancer triple-negative breast cancer tumour microenvironment HAVCR2 sEVs M2-associated marker
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Impact of Germline BRCA1/2 Mutations on Clinical Outcomes in Metastatic Triple-Negative Breast Cancer Patients Treated with Sacituzumab Govitecan—An International CEBCC Study from Poland,the Czech Republic and Slovakia 认领 引用
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作者 Renata Pacholczak-Madej Mirosława Püsküllüoğlu +24 位作者 Anna Polakiewicz-Gilowska Małgorzata Pieniążek Iveta Kolářová Miroslava Malejčíková Lenka Rušinová MilošHolánek Renata Soumarová Karolina Winsko-Szczęsnowicz JustynaŻubrowska Aleksandra Konieczna Agnieszka Młodzińska Daniel Krejčí Iwona Danielewicz Magdalena Szymanik-Resko Tomasz Ciszewski Maja Lisik-Habib Anika Pękala HanaŠtudentová JanŠustr Bogumiła Czartoryska-Arłukowicz AleksandraŁacko Jolanta Smok-Kalwat MichałJarząb Zuzana Bielčiková Marcin Kubeczko 《Oncology Research》 SCIE 2026年第6期457-470,共14页
Background:Germline breast cancer susceptibility gene 1/2(BRCA1/2)variants guide breast cancer treatment,but their clinical relevance in metastatic triple-negative breast cancer(mTNBC)treated with sacituzumab goviteca... Background:Germline breast cancer susceptibility gene 1/2(BRCA1/2)variants guide breast cancer treatment,but their clinical relevance in metastatic triple-negative breast cancer(mTNBC)treated with sacituzumab govitecan(SG)remains unclear.The study aimed to evaluate the association between BRCA status and outcomes in SG-treated mTNBC.Methods:We retrospectively analyzed 264 patients with mTNBC and known germline BRCA1/2(gBRCA1/2)status who received SG between August 2021 and May 2025 across multiple oncology centers in Poland,the Czech Republic and Slovakia.Survival outcomes were compared between patients with gBRCA1/2 mutations(gBRCA1/2m)and those with gBRCA1/2 wild-type(gBRCA1/2wt)using Kaplan–Meier estimates,the log-rank test,and multivariable Cox proportional hazards models.Two-sided p<0.05 was considered statistically significant.Results:Among 264 patients,35(13.3%)were gBRCA1/2m and 229(86.7%)were gBRCA1/2wt.After a median follow-up of 9.9 months,the median progression-free survival(PFS)was 4.5 months(95%confidence interval[CI]2.1–6.3)in gBRCA1/2 carriers versus 4.2 months(95%CI 3.5–5.8)in gBRCA1/2wt patients(p=0.10).Median overall survival(OS)was 9.1 months(95%CI 5.0–15.1)in gBRCA1/2 carriers compared to 11.5 months(95%CI 10.3–13.5)in gBRCA1/2wt patients(p=0.26).Brain metastases were more frequent in carriers(20%vs.8.3%,p=0.06).In multivariable analysis,Eastern Cooperative Oncology Group(ECOG)performance status was the only independent predictor of poorer survival(hazard ratio 1.97,95%CI 1.42–2.74,p<0.01),while gBRCA1/2 status showed no independent association.Conclusions:In this large retrospective cohort of mTNBC patients treated with SG,the presence of gBRCA1/2 was not associated with statistically significant differences in PFS or OS. 展开更多
关键词 Triple-negative breast cancer sacituzumab govitecan BRCA1/2 germline mutations real-world evidence international multicenter cohort
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Hypoxia facilitates triple-negative breast cancer stem cellsenrichment and stemness maintenance through oxidized ataxiatelangiectasia mutated-induced one-carbon metabolism 认领 引用
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作者 Dan Yang Yu-Lian Ou +4 位作者 Shu-Hui Wang Hong-Jun Jin Su-Hua Chen Ran Han Hua Zhang 《World Journal of Stem Cells》 SCIE 2026年第1期66-83,共18页
BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes... BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment. 展开更多
关键词 Hypoxia Oxidized ataxia telangiectasia mutated Cancer stem cells Triple-negative breast cancer One-carbon metabolism Methylenetetrahydrofolate dehydrogenase 2 Serine hydroxymethyltransferase 2
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ZMIZ2/MCM3 Axis Participates in Triple-Negative Breast Cancer Progression 认领 引用
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作者 Xiaopan Zou Meiyang Sun +3 位作者 Xin Jiang Jingze Yu Xiaomeng Li Bingyu Nie 《Oncology Research》 SCIE 2026年第1期297-324,共28页
Objective:Triple-negative breast cancer(TNBC)is highly aggressive and lacks an effective targeted therapy.This study aimed to elucidate the functions and possible mechanisms of action of zinc finger miz-type containin... Objective:Triple-negative breast cancer(TNBC)is highly aggressive and lacks an effective targeted therapy.This study aimed to elucidate the functions and possible mechanisms of action of zinc finger miz-type containing 2(ZMIZ2)and minichromosome maintenance complex component 3(MCM3)in TNBC progression.Methods:The relationship between ZMIZ2 expression and clinical characteristics of TNBC was investigated.In vitro and in vivo experiments were performed to investigate the role of ZMIZ2 dysregulation in TNBC cell malignant behaviors.The regulatory relationship between ZMIZ2 and MCM3 was also explored.Transcriptome sequencing was performed to elucidate possible mechanisms underlying the ZMIZ2/MCM3 axis in TNBC.Results:High ZMIZ2 expression levels were associated with the malignant degree of TNBC.ZMIZ2 overexpression promoted TNBC cell proliferation,migration,and invasion;inhibited apoptosis;and induced G1 phase cell cycle arrest,whereas knockdown of ZMIZ2 had the opposite effect.ZMIZ2 directly targeted and positively regulated MCM3 expression.MCM3 knockdown reversed the effect of ZMIZ2 overexpression on TNBC tumor growth both in vitro and in vivo.High MCM3 expression levels were linked to the degree of malignancy and poor prognosis in TNBC.The differentially expressed genes associated with the ZMIZ2/MCM3 axis were significantly enriched in multiple pathways,such as the mitogen-activated protein kinase(MAPK),mechanistic target of rapamycin(mTOR),Wnt,and Ras signaling pathways,as verified by The Cancer Genome Atlas data.Conclusions:ZMIZ2 and MCM3 were highly expressed in TNBC.ZMIZ2 promoted the development by positively regulating MCM3 expression.Key pathways,such as the Ras/MAPK,phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mTOR,and Wnt signaling pathways,may be key downstreammechanisms. 展开更多
关键词 Triple-negative breast cancer zinc finger miz-type containing 2 minichromosome maintenance complex component 3 pathway enrichment analysis
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Mistletoe Lectin Overcomes Macrophage-Mediated Chemo-Resistance in 3D Co-Culture Models of Triple-Negative Breast Cancer 认领 引用
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作者 Chang-Eui Hong Su-Yun Lyu 《BIOCELL》 SCIE 2026年第2期199-223,共25页
Objective Tumor-associated macrophages(TAMs)contribute to chemoresistance in triple-negative breast cancer(TNBC),yet strategies to reprogram TAMs while enhancing chemotherapy efficacy remain limited.This study investi... Objective Tumor-associated macrophages(TAMs)contribute to chemoresistance in triple-negative breast cancer(TNBC),yet strategies to reprogram TAMs while enhancing chemotherapy efficacy remain limited.This study investigated whether Viscum album L.var.coloratum agglutinin(VCA)could sensitize TNBC cells to doxorubicin(DOX)and modulate TAM-mediated chemoresistance in three-dimensional(3D)co-culture models.Methods MDA-MB-231 TNBC cells were co-cultured with RAW264.7 macrophages in collagen-embedded 3D spheroids.Spheroid viability was assessed using an ATP-based luminescent assay.Cytokine secretion and epithelial-mesenchymal transition(EMT)markers were measured using ELISA and Western blotting.Drug synergy was evaluated using combination index(CI)calculations.Results VCA-DOX combination demonstrated synergistic cytotoxicity exclusively in co-culture spheroids(CI=0.72),reducing viability to 25.9%(p<0.001),while showing no synergy in monoculture(CI=1.52).Combination treatment decreased VEGF secretion by 49%and IL-6 by 74%,while elevating TNF-α2.7-fold,suggesting macrophage reprogramming.VCA enhanced E-cadherin expression while suppressing mesenchymal markers in co-culture spheroids and reduced Matrigel invasion by 60%(p<0.001).Conclusion VCA-DOX combination demonstrates synergistic anticancer effects through TAM reprogramming and enhanced chemosensitization specifically in 3D co-culture models,warranting further investigation for overcoming macrophage-mediated chemoresistance in TNBC. 展开更多
关键词 Korean mistletoelectin triple-negative breast cancer doxorubicin combination therapy
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Advanced nanosystem for target recognition and precise dual-mode imaging-guided photothermal therapy against triple-negative breast cancer 认领 引用
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作者 Lei Li Annan Liu +6 位作者 Gang Wei Xingchen Li Hao Liang Maja D.Nešić Ze Wang Hui Guo Quan Lin 《Chinese Chemical Letters》 SCIE CAS CSCD 2026年第2期289-296,共8页
Triple-negative breast cancer(TNBC)presents significant diagnostic and therapeutic challenges due to the lack of targeted treatments,rapid progression,high recurrence and metastasis rates,and overall poorer prognosis.... Triple-negative breast cancer(TNBC)presents significant diagnostic and therapeutic challenges due to the lack of targeted treatments,rapid progression,high recurrence and metastasis rates,and overall poorer prognosis.Herein,the targeted theranostic platform of cysteine-modified gold nanodots-sulfhydrated luteinizing hormone releasing hormone(CGN-SLR)nanosystem was designed for target recognition and precise dual-mode imaging-guided photothermal therapy(PTT)against TNBC.On the one hand,the CGN-SLR nanosystem can serve as an ideal targeting fluorescent probe and computed tomography(CT)enhancer to facilitate the accurate diagnosis and surgical guidance of TNBC.On the other hand,the CGN-SLR nanosystem with great targeting and PTT ability can significantly inhibit the growth of TNBC,without causing harm to normal tissues and healthy organs.It provides an effective strategy for the diagnosis and treatment of TNBC through the rational design of multifunctional nanoplatform with target recognition,multiple imaging guidance/monitoring,and high-efficiency PTT. 展开更多
关键词 Nanodots Triple-negative breast cancer Tumor targeting Imaging-guided Photothermal therapy
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Ramulus Mori alkaloids(SZ-A)sensitize triple-negative breast cancer to cisplatin via PLA2G2A-mediated ceramide metabolism 认领 引用
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作者 Chen Chao Wan Mengqi +10 位作者 Zhu Zhixu Xie Zhaoyu Zhang Yu Xu Tao Meng Han Wu Miaomiao Gui Liangfeng Lv Hongbo Wang Guodong Han Jun Che Hui 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2026年第8期972-986,共15页
Cisplatin(DDP)remains a standard therapy for triple-negative breast cancer(TNBC),yet intrinsic or acquired resistance often limits its efficacy;here,we report that Ramulus Mori alkaloids(SZ-A),an approved botanicalα-... Cisplatin(DDP)remains a standard therapy for triple-negative breast cancer(TNBC),yet intrinsic or acquired resistance often limits its efficacy;here,we report that Ramulus Mori alkaloids(SZ-A),an approved botanicalα-glucosidase inhibitors,synergize with DDP to suppress TNBC progression in vitro and in vivo by driving PLA2G2A-dependent ceramide accumulation.Combining SZ-A with DDP synergistically inhibits viability,clonogenicity,migration,and invasion,induces S-phase arrest and apoptosis,and attenuates tumor growth in xenograft models.Mechanistically,SZ-A directly binds to and stabilizes PLA2G2A,blocking its autophagic-lysosomal degradation,leading to accumulated PLA2G2A that suppresses fatty acid oxidation and triggers ceramide accrual via ADIPOR2 inhibition.Genetic ablation of PLA2G2A abrogates these effects.DDP further enhances SZ-A-induced PLA2G2A upregulation and ceramide accumulation,resulting amplified cytotoxicity.Our findings reveal SZ-A as a chemosensitizing agent that enhances the efficacy of DDP in TNBC. 展开更多
关键词 Ramulus Mori alkaloids Triple-negative breast cancer(TNBC) Cisplatin Phospholipase A2 Group IIA(PLA2G2A) Ceramide
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The ethyl acetate extract from Trichoderma viride fermentation acts by downregulating the leukocyte transendothelial migration signaling pathway to induce ferroptosis in triple-negative breast cancer cells 认领 引用
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作者 Yu Kuang Bai-Hui Lu +5 位作者 Jia-Yi Wu Song-Yu Wu Hai-Yan Fu Qing-Yan Nan Jing Li Xiao-Long Yang 《Natural Products and Bioprospecting》 CSCD 2026年第1期243-258,共16页
Purpose Triple-negative breast cancer(TNBC),characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor receptor 2(HER2)expression,remains clinically challenging d... Purpose Triple-negative breast cancer(TNBC),characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor receptor 2(HER2)expression,remains clinically challenging due to the lack of effective targeted therapies.This investigation revealed the anti-TNBC potential of Trichoderma viride ethyl acetate extract(TVEAE)from the endophytic fungus Trichoderma viride isolated from Coreopsis basalis.Methods Pharmacological validation ofTVEAE's anti-TNBC efficacy was conducted through in vitro and in vivo phar-macological models.The cell death mechanisms were systematically investigated using Hoechst staining,reactive oxygen species(ROS)detection,and lipid peroxidation assays.Potential therapeutic targets and signaling pathways were identified by integrating network pharmacology,transcriptomics,and weighted gene co-expression network analysis(WGCNA).Furthermore,this study validated key tumor-related proteins involved in tumor progression and cell death pathways via Western blotting.Finally,chemical constituents were characterized through molecular network coupled with Global Natural Products Social Molecular Networking(GNPS)analysis.Results Both in vitro and in vivo models established TVEAE's significant anti-TNBC efficacy.Mechanistic interrogation established TVEAE-mediated ferroptosis induction via selective modulation of leukocyte transendothelial migration(TEM)signaling cascades.Integrative analysis combining transcriptomics,WGCNA,and network pharmacology identified IL-6/TNF-α/HSP90AA1 as core therapeutic targets regulating TEM pathway dynamics.GNPS-assisted molecular network-ing uncovered six structurally novel anti-TNBC metabolites,including N-lauryldiethanolamine,erucamide,and Gliotoxin.Conclusion This study provides the first evidence ofTVEAE's anti-TNBC activity through multi-target engagement along the leukocyteTEM signaling axis,effectively triggering ferroptosis.The mechanistic elucidation advances TNBC therapeutic development,offering a multi-dimensional targeting strategy against this recalcitrant malignancy. 展开更多
关键词 Trichoderma viride Triple-negative breast cancer Leukocyte transendothelial migration Ferroptosis
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Prognosis and Immunotherapy Effect of Triple-Negative Breast Cancer by Lactylation-Related Genes and Experimental Validation 认领 引用
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作者 Yang Wang Ying Xie +7 位作者 Yiyi Ye Youyang Shi Feifei Li Mengdie Zhu Ciyi Hua Yuan Xu Rui Yang Sheng Liu 《Oncology Research》 SCIE 2026年第7期688-712,共25页
Background Triple-negative breast cancer(TNBC)is an aggressive subtype of breast malignancy characterized by poor clinical outcomes and limited therapeutic options.The identification of reliable biomarkers for predict... Background Triple-negative breast cancer(TNBC)is an aggressive subtype of breast malignancy characterized by poor clinical outcomes and limited therapeutic options.The identification of reliable biomarkers for predicting prognosis and immunotherapeutic response remains an urgent clinical need.This study aimed to develop an integrative lactylation-related gene signature to simultaneously evaluate prognostic trajectories and immunotherapeutic sensitivity in TNBC.Methods Transcriptomic and clinical data from public TNBC cohorts were systematically analyzed.Lactylation-related gene signatures were used to stratify patients via consensus clustering.A scoring model was constructed based on differentially expressed genes between clusters,and its associations with immune infiltration,pathway enrichment,drug sensitivity,and clinical outcomes were evaluated.Finally,quantitative real-time polymerase chain reaction,Western blot and Confocal immunofluorescence Microscopy were used to validate the hub genes.Results Significant gene expression differences stratified TNBC patients into high-and low-score groups,with the high-score group demonstrating superior clinical outcomes.These patients also showed better responses to immunotherapy,as indicated by immune checkpoint profiles and chemotherapy sensitivity.Experimental validation confirmed Programmed Cell Death 1 Ligand 2,Immunoglobulin J Chain,and Colony Stimulating Factor 2 Receptor Beta as key molecular nodes.Our scoring model predicts immunotherapy efficacy,and these three genes may represent potential candidates for further therapeutic exploration in TNBC.Conclusions This study establishes a novel lactylation-related gene signature that effectively predicts both prognosis and immunotherapeutic sensitivity in TNBC.The identified hub genes represent promising biomarkers and potential therapeutic targets warranting further investigation. 展开更多
关键词 Triple-negative breast cancer(TNBC) lactylation immune infiltration prognosis differentially expressed genes
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Capecitabine and Huaier granule intensive therapy:clinical effectiveness and prognosis in patients with triple-negative breast cancer receiving conventional treatment 认领 引用
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作者 Zhen-Zhen Bu De-Hong Yu +5 位作者 Zhuang Zhu Wen-Han Zhang Dong-Shen Ma Ruo-Fei Wang Xiao-Xiao Liu Long-Zhen Zhang 《Traditional Medicine Research》 2026年第10期47-58,共12页
Background:Triple-negative breast cancer is the most malignant among all types of breast cancer.Patients with triple-negative breast cancer(TNBC)have limited therapeutic options following standard treatment(surgery,ne... Background:Triple-negative breast cancer is the most malignant among all types of breast cancer.Patients with triple-negative breast cancer(TNBC)have limited therapeutic options following standard treatment(surgery,neoadjuvant/adjuvant chemotherapy,and radiotherapy).Capecitabine and Huaier granule are both drugs used in the conventional treatment stage for TNBC.This study investigated the efficacy and toxicity of intense therapy with capecitabine and/or Huaier granule in TNBC patients after conventional treatment.Methods:From January 2011 to October 2023,data were collected retrospectively from patients at the Affiliated Hospital of Xuzhou Medical University who had TNBC with clinical stages I-III.These patients had surgery and successfully finished standard adjuvant chemotherapy with anthracycline and/or taxanes.Patients were categorized into four groups based on intensive therapy:capecitabine monotherapy(n=92),Huaier granule monotherapy(n=79),combination therapy(n=87),and observation(n=90).Results:Among the 348 patients with TNBC treated at Xuzhou Medical University’s Affiliated Hospital,the capecitabine group,the Huaier granule group,the capecitabine combined with Huaier granule group(the combination group),and the observation group had 5-year progression-free survival(PFS)of 64.6%,65.8%,86.3%,and 41.8%.The 5-year overall survival(OS)rates were 81.5%,92.5%,94.5%,and 69.8%,respectively.The combination group showed significantly superior PFS and OS compared to all other groups(P<0.01).Combination therapy significantly reduced capecitabine-associated adverse events:hand-foot syndrome(11.5%vs 54.3%),leukopenia(16.1%vs 28.3%),and abdominal pain/diarrhea(2.3%vs 20.7%).Conclusion:Intensive therapy with capecitabine and/or Huaier granule,particularly the combination regimen,significantly improved survival outcomes in TNBC patients after standard treatment.The combination also markedly reduced the adverse events associated with capecitabine monotherapy. 展开更多
关键词 triple-negative breast cancer Huaier granule capecitabine intensive treatment progression-free survival overall survival adverse events
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Extracellular Signal-Regulated Kinase and Reactive Oxygen Species Regulate PD-L1 to Promote Migration and Proliferation of Triple-Negative Breast Cancer MDA-MB-231 Cells 认领 引用
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作者 Ching-Chun Ho Yen-Cheng Chen +1 位作者 Wei-Liang Lean Wen-Sheng Wu 《Oncology Research》 SCIE 2026年第8期355-371,共17页
Objectives:Triple-negative breast cancer(TNBC)is a highly aggressive form of breast cancer.Mitogen-activated protein kinases(MAPKs),including extracellular signal-regulated kinase(ERK)and c-Jun N-terminal kinase(JNK),... Objectives:Triple-negative breast cancer(TNBC)is a highly aggressive form of breast cancer.Mitogen-activated protein kinases(MAPKs),including extracellular signal-regulated kinase(ERK)and c-Jun N-terminal kinase(JNK),as well as protein kinase B(AKT),are potential therapeutic targets for TNBC.Programmed death-ligand 1(PD-L1)is implicated in TNBC progression and is associated with AKT and ERK signaling pathways.In addition,reactive oxygen species(ROS)act upstream of MAPK/AKT and PD-L1.In this study,we aimed to clarify the role of PD-L1 in TNBC progression and to delineate the underlying signaling mechanisms.Methods:Western blotting and reverse transcription-polymerase chain reaction were used to analyze protein and mRNA levels,respectively.Transwell migration and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide(MTT)assays were used to assess cell migration and proliferation,respectively.Results:The ERK inhibitor(PD98059)suppressed MDA-MB-231 cell migration but not proliferation,whereas PD-L1 siRNA and the ROS scavenger dithiothreitol(DTT)reduced both cell migration and proliferation.However,PD-L1 siRNA and DTT did not reduce the activities of ERK,JNK,or AKT.Whereas PD98059 and DTT suppressed PD-L1 protein expression,PD-L1 mRNA expression could be reduced by DTT only.Taken together,ROS and ERK may activate different pathways to regulate PD-L1 expression and MDA-MB-231 cell progression.Consistently,DTT combined with PD98059 additively inhibited MDA-MB-231 cell migration.Similar observations were noted in another TNBC cell line,Hs578T,which exhibits motility,but not in MDA-MB-453 cells,which lack motility.Conclusion:Since PD-L1 appears to function downstream of ERK and ROS and is required for TNBC progression,co-targeting both ERK and ROS signaling pathways may represent a promising therapeutic strategy for TNBC. 展开更多
关键词 Triple-negative breast cancer programmed death-ligand 1 extracellular signal-regulated kinase reactive oxygen species signal transduction targeted therapy
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PARK2-Mediated PGK1 Degradation Suppresses Partial Epithelial-Mesenchymal Transition and Metastasis in Triple-Negative Breast Cancer 认领 引用
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作者 Zhengzheng Li Haitong Xie +4 位作者 Yujuan Chen Qiuyan Li Xing Yuan Xinyue Dai Jie Chen 《Oncology Research》 SCIE 2026年第7期567-594,共28页
Objectives:Triple-negative breast cancer(TNBC)is an aggressive subtype lacking targeted therapies.Phosphoglycerate kinase 1(PGK1)drives TNBC progression,but mechanisms governing its protein stability remain unclear.Th... Objectives:Triple-negative breast cancer(TNBC)is an aggressive subtype lacking targeted therapies.Phosphoglycerate kinase 1(PGK1)drives TNBC progression,but mechanisms governing its protein stability remain unclear.This study aims to identify the E3 ubiquitin ligase responsible for PGK1 degradation and evaluate its therapeutic potential against metastasis.Methods:Clinical datasets and 50 human TNBC tissues were analyzed via multiplex immunohistochemistry.Co-immunoprecipitation,ubiquitination linkage assays,and structural modeling were utilized for in vitro mechanistic studies in TNBC cells.Additionally,functional impacts on epithelial-mesenchymal transition(EMT)and metastasis were evaluated using transwell assays and an in vivo mouse lung metastasis model.Results:Parkinson disease protein 2(PARK2)is a novel E3 ubiquitin ligase that mediates proteasomal degradation of PGK1 in TNBC cells.Elevated PGK1 expression and reduced PARK2 expression in TNBC,with high PGK1 levels correlating with unfavorable overall survival(HR:2.138,95%CI:1.001 to 4.569,p=0.049).PARK2 physically binds PGK1 via its RING2 domain and promotes K48-linked polyubiquitination,leading to proteasomal degradation.A significant negative correlation between PARK2 and PGK1 at the protein levels were confirmed in 50 TNBC tumor tissues(Spearman’s rho=−0.58,p<0.001).Functionally,PARK2 overexpression reduced mesenchymal markers(Vimentin,Snail1,Slug)and suppressed migration and invasion of TNBC cells,effects that were reversed by PGK1 overexpression.PARK2 significantly inhibited PGK1-mediated lung metastasis in in vivo tail vein injection models Conclusion:These findings establish the PARK2-PGK1 axis as a critical regulator of partial epithelial-mesenchymal transition and metastasis in TNBC,suggesting that strategies to enhance PARK2 expression or activity may represent promising therapeutic approaches for this aggressive breast cancer subtype. 展开更多
关键词 Triple-negative breast cancer(TNBC) phosphoglycerate kinase 1(PGK1) Parkinson disease protein 2(PARK2) proteasomal degradation epithelial-to-mesenchymal transition metastasis
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BHLHE40 Is a Transcriptional Regulatory Target of NFE2L3 in Triple-Negative Breast Cancer 认领 引用
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作者 Shail Rakesh Modi Terrick Andey George Acquaah-Mensah 《Oncology Research》 SCIE 2026年第2期346-378,共33页
Objectives:The current treatment options and therapeutic targets for triple-negative breast cancer(TNBC),an aggressive subtype of breast cancer(BrCA),are limited.This study aimed to identify novel biomarkers and trans... Objectives:The current treatment options and therapeutic targets for triple-negative breast cancer(TNBC),an aggressive subtype of breast cancer(BrCA),are limited.This study aimed to identify novel biomarkers and transcriptional regulatory networks(TRN)inherent in TNBC samples.Methods:We analyzed pan-cancer BrCA datasets from The Cancer Genome Atlas(TCGA)to compare triple-positive breast cancer(TPBC)with TNBC.TRN algorithms and virtual inference of protein-enriched regulon(VIPER)were used to identify master regulators and their target genes.Utilizing TNBC cells(MDA-MB-231 and MDA-MB-468),we validated the relationship of nuclear factor erythroid 2-like 3(NFE2L3)and basic helix-loop-helix family member E 40(BHLHE40)by performing a luciferase assay.The expression levels of these targets were measured after transfections with plasmid and siRNA via qRT-PCR and western blots.The effect of these genes on cell proliferation and migration was studied using phenotypic assays.Results:Using computational approaches,we identified NFE2L3 as a master regulator with BHLHE40 as its target gene.NFE2L3 protein binds to the promoter region of BHLHE40 and regulates its transcriptional activity.Additionally,silencing and overexpressing NFE2L3 and BHLHE40 in TNBC cell lines MDA-MB-231 and MDA-MB-468 showed that NFE2L3 directly regulates BHLHE40 at both transcriptional and translational levels.We found that BHLHE40 requires NFE2L3 for cell proliferation and migration in TNBC.Conclusion:These findings underscore the significance of NFE2L3 and BHLHE40 in TNBC,highlighting NFE2L3’s role in regulating the oncogenic activity of BHLHE40 in TNBC cells. 展开更多
关键词 Nuclear factor erythroid 2-like 3(NFE2L3/NRF3) basic helix-loop-helix family member E 40(BHLHE40/DEC1) triple-negative breast cancer transcriptional regulatory networks master regulators
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Cancer stem cell markers, chemotherapy response, and survival in triple-negative breast cancer 认领 引用
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作者 Faisal Nabi Depar Ahmed Jamal Chaudhary +7 位作者 Jawad Hameed Faisal Sarwar Abbasi Bibi Uzma Amjad Ali Naheed Akhtar Rizwan Khan Afsheen Siddiqi Sohail Riaz 《World Journal of Clinical Oncology》 2026年第2期165-174,共10页
BACKGROUND Triple-negative breast cancer(TNBC)is an aggressive subtype with limited therapeutic options,primarily relying on chemotherapy,yet often leading to recurrence due to chemoresistance.Cancer stem cells(CSCs)c... BACKGROUND Triple-negative breast cancer(TNBC)is an aggressive subtype with limited therapeutic options,primarily relying on chemotherapy,yet often leading to recurrence due to chemoresistance.Cancer stem cells(CSCs)contribute to tumor heterogeneity,resistance,and poor prognosis,but data in Pakistani populations are scarce.This study hypothesizes that a positive CSC phenotype independently predicts reduced pathological complete response(pCR)and inferior survival outcomes.AIM To investigate CSC markers’association with chemotherapy response and survival in Pakistani TNBC patients.METHODS Retrospective cohort study at Institute of Radiotherapy and Nuclear Medicine,Peshawar,Pakistan,including 256 women with TNBC from January 2015 to December 2022.CSC markers(CD44 high,CD24 low,aldehyde dehydrogenase 1 positive)were assessed via immunohistochemistry on pre-treatment biopsies.Outcomes:pCR to neoadjuvant chemotherapy,overall survival,disease-free survival.Data were analyzed with multivariable logistic regression and Cox proportional hazards models,adjusting for age,tumor grade,and stage.RESULTS The CSC-positive phenotype was identified in 26 patients(10.2%).Compared to negative cases,positive cases had lower pCR rates[5.0%vs 51.8%;adjusted odds ratio=0.05,95%confidence interval(CI):0.01-0.39,P=0.004].The positive phenotype was associated with poorer overall survival(adjusted hazard ratio=4.35,95%CI:2.43-7.79,P<0.001),with a median overall survival of 19 months vs 27 months.No association with disease-free survival was observed(hazard ratio=0.86,95%CI:0.43-1.73,P=0.675).CONCLUSION CSC markers are associated with reduced chemotherapy response and inferior overall survival in Pakistani TNBC patients.These findings suggest their potential as prognostic biomarkers and highlight the need for future research into targeted strategies,such as proteomic profiling and Proteolysis Targeting Chimeras technology,to overcome chemoresistance in this population. 展开更多
关键词 Triple-negative breast cancer Cancer stem cells CD44 CD24 Aldehyde dehydrogenase 1 Chemotherapy response Survival Pakistan
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Letter to the Editor:Cancer stem cell and oncomatrix biomarkers predict chemotherapy response and survival in triple-negative breast cancer 认领 引用
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作者 Ilya Klabukov Denis Baranovskii +1 位作者 Daria Eygel Elena Yatsenko 《World Journal of Clinical Oncology》 2026年第7期154-157,共4页
We read with great interest the clinical study published in the World Journal of Clinical Oncology by Depar et al investigated the associations of cancer stem cells(CSC)markers(CD44,CD24,ALDH1)with chemotherapy respon... We read with great interest the clinical study published in the World Journal of Clinical Oncology by Depar et al investigated the associations of cancer stem cells(CSC)markers(CD44,CD24,ALDH1)with chemotherapy response and survival in triple-negative breast cancer(TNBC)patients.Current advanced approaches for the treatment of chemoresistant TNBC focus on mRNA-based therapy as a form of personalized medicine designed to overcome conventional therapeutic resistance.Among the clinical findings,the study by Depar et al also focuses on the availability of personalized medicine alternatives for patients with hard-tocure cancers,using Pakistan as an example of a developing economy.Beyond the other findings of the study,one particular idea is worth noting:Advanced diagnostics are needed not to replace current approaches,but to be applied in lowincome economies that cannot afford high-cost diagnostic methods.Indeed,the development of expensive therapies for resistant cancers has been limited in effectiveness by population-specific genetic patterns.Screening studies aimed at identifying substitute biomarkers associated with the CSC microenvironment or tumor extracellular matrix properties could provide a basis for selecting personalized therapies.This"leapfrogging"approach appears to be especially beneficial for high-risk patients with chemoresistant TNBC. 展开更多
关键词 Breast cancer Cancer Cancer stem cells Cell regulation Epithelial-mesenchymal transition Extracellular matrix Leapfrogging Personalized medicine Triple-negative breast cancer Tumor
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Prognostic significance of stem cell markers:In triple-negative breast cancers 认领 引用
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作者 Sunil V Jagtap Shubham S Jagtap 《World Journal of Clinical Oncology》 2026年第7期11-16,共6页
Triple-negative breast cancer(TNBC)is defined by the lack of expression of estrogen receptor,progesterone receptor,and human epidermal growth factor receptor-2.Investigating the role of cancer stem cell(CSC)markers in... Triple-negative breast cancer(TNBC)is defined by the lack of expression of estrogen receptor,progesterone receptor,and human epidermal growth factor receptor-2.Investigating the role of cancer stem cell(CSC)markers in TNBC carcinogenesis and tumor progression is of increasing interest.TNBC cells have been reported to exhibit CSC characteristics at functional,molecular,and transcriptional levels.Several stemness markers have been described across different histological subtypes of breast cancer,including CD44,CD24,CD133,EpCAM,CD166,Lgr5,CD47,ALDH1,and ABCG2.Recent studies have demonstrated that CD133 positivity enables the identification of CSC populations in breast cancer.These markers may have enhanced prognostic value if TNBC tumors are further stratified into molecular subtypes,particularly through evaluation of their expression in the mesenchymal stem-like subtype.In this article,we comment on the article by Depar et al published in the World Journal of Clinical Oncology. 展开更多
关键词 Triple-negative breast cancer Cancer stem cell Bio-markers Prognostic Significance
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