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
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
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
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
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
Triple-negative breast cancer(TNBC)is currently the most heterogeneous and aggressive breast cancer type.It has a high recurrence rate,poor clinical prospects,and lack of predictive markers and potential treatment opt...Triple-negative breast cancer(TNBC)is currently the most heterogeneous and aggressive breast cancer type.It has a high recurrence rate,poor clinical prospects,and lack of predictive markers and potential treatment options.Dysregulated microRNAs(miRNAs)are involved in various cellular processes in TNBC.Moreover,variations in the miRNA levels in TNBC may act as a dependable indicator for predicting the effectiveness and specificity of treatments.Currently,the application of miRNAs for breast cancer therapy is primarily in the preclinical stage,with a focus on identifying highly specific and sensitive miRNAs that could offer new possibilities for early diagnosis,clinical treat-ment,and prognostic monitoring of TNBC.展开更多
Objective:Triple-negative breast cancer(TNBC)is a highly aggressive subtype that lacks targeted therapies,leading to a poorer prognosis.However,some patients achieve long-term recurrence-free survival(RFS),offering va...Objective:Triple-negative breast cancer(TNBC)is a highly aggressive subtype that lacks targeted therapies,leading to a poorer prognosis.However,some patients achieve long-term recurrence-free survival(RFS),offering valuable insights into tumor biology and potential treatment strategies.Methods:We conducted a comprehensive multi-omics analysis of 132 patients with American Joint Committee on Cancer(AJCC)stage III TNBC,comprising 36 long-term survivors(RFS≥8 years),62 moderate-term survivors(RFS:3-8 years),and 34 short-term survivors(RFS<3 years).Analyses investigated clinicopathological factors,whole-exome sequencing,germline mutations,copy number alterations(CNAs),RNA sequences,and metabolomic profiles.Results:Long-term survivors exhibited fewer metastatic regional lymph nodes,along with tumors showing reduced stromal fibrosis and lower Ki67 index.Molecularly,these tumors exhibited multiple alterations in genes related to homologous recombination repair,with higher frequencies of germline mutations and somatic CNAs.Additionally,tumors from long-term survivors demonstrated significant downregulation of the RTK-RAS signaling pathway.Metabolomic profiling revealed decreased levels of lipids and carbohydrate,particularly those involved in glycerophospholipid,fructose,and mannose metabolism,in long-term survival group.Multivariate Cox analysis identified fibrosis[hazard ratio(HR):12.70,95%confidence interval(95%CI):2.19-73.54,P=0.005]and RAC1copy number loss/deletion(HR:0.22,95%CI:0.06-0.83,P=0.026)as independent predictors of RFS.Higher fructose/mannose metabolism was associated with worse overall survival(HR:1.30,95%CI:1.01-1.68,P=0.045).Our findings emphasize the association between biological determinants and prolonged survival in patients with TNBC.Conclusions:Our study systematically identified the key molecular and metabolic features associated with prolonged survival in AJCC stage III TNBC,suggesting potential therapeutic targets to improve patient outcomes.展开更多
Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer(TNBC)therapy.Ho...Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer(TNBC)therapy.However,the ferroptosis accompanied with down-regulation of glutathione peroxidase 4(GPX4)lead to CD36-mediated tumor-infiltrating CD8^(+)T cells uptaking fatty acids,resulting in the negative action on immunotherapeutic efficacy.Herein,the albumin nanoparticles,abbreviated as LHS NPs,were designed by co-assembly of hemin,linoleic acid-cystamine,and a CD36 inhibitor sulfosuccinimide oleate,to bi-directionally manipulated ferroptosis in tumor and CD8^(+)T cells for TNBC therapy.LHS NPs exerted more efficient reactive oxygen species generation,glutathione depletion and malondialdehyde production by the combinatory strategy of classical and non-classical ferroptosis modes,which amplified the positive action on ferroptosis in tumor cells.Meanwhile,LHS manipulated the negative action of ferroptosis by inhibiting the CD36 mediated-lipid peroxidation in CD8^(+)T cells,thereby activating the immunotherapeutic efficacy with the improvements on induction of immunogenic cell death,proliferation of CD4+CD8^(+)T cells and natural killer cells,alleviation immunosuppressive regulatory T cells and myeloid-derived suppressor cells,and repolarization of the M2-to M1-phenotype tumor-associated macrophages.Thus,LHS NPs demonstrated an improved antitumor efficacy in suppressing the tumor growth and lungmetastasis of 4T1-tumormice.Our work gives novel insights for the bi-directionally manipulating ferroptosis in tumor and CD8^(+)T cells on TNBC chemoimmunotherapy.展开更多
Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side ...Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side effects.Astragalus polysaccharide(APS)is one of the active components extracted from Astragalus membranaceus and has gained attention for its various biological properties.This research is aimed to evaluate the effectiveness of a combination of APS and DDP on TNBC and explore the potential mechanisms.Methods:The efficacy and mechanisms of single or combined treatment were evaluated using Cell Counting Kit-8(CCK8)assay,Annexin V-fluorescein isothiocyanate(FITC)/propidium iodide(PI)staining,wound healing assay,trans-well invasion/migration assay,hematoxylin-eosin(HE)staining,immunohistochemical(IHC)staining,Western Blot(WB)analysis,and fluorescence-activated cell sorting(FACS).An orthotopic model of TNBC was used to assess the in vivo treatment efficacy of single or combination treatment.Results:APS significantly enhanced the anti-proliferative,anti-migratory,and anti-invasive effects of DDP on TNBC cells.The combination of APS and DDP downregulated anti-apoptotic genes(Bcl2 and Bcl-xL)while upregulating pro-apoptotic genes(Puma,Cle-Caspase3,Cle-PARP),leading to enhanced apoptosis.This combination treatment increased E-cadherin levels,decreased Vimentin,Snail,Slug,and Twist levels,and effectively suppressed epithelial-mesenchymal transition(EMT)-associated cell invasion.In the orthotopic model of TNBC,a synergistic reduction in tumor growth was observed in mice treated with APS and DDP.Additionally,the combination of APS and DDP induced the infiltration of CD8+T lymphocytes into the tumor immune microenvironment.Conclusion:The combination of APS and DDP exhibits more potent tumor inhibition and anti-tumor immunity than either agent alone,representing a novel approach to enhance therapeutic efficacy without increasing the side effects of DDP.展开更多
Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autoph...Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autophagy is an important process for maintaining cellular homeostasis,and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors.In contrast to targeting protein activity,intervention with proteinprotein interaction(PPI)can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.Methods:Here,we employed Naive Bayes,Decision Tree,and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC,aiming to uncover novel therapeutic targets.Meanwhile,the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay,and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection.Colony formation,cellular immunofluorescence,cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.Results:By developing three PPI classification models and analyzing over 13,000 datasets,we identified 3733 previously unknown autophagy-related PPIs.Our network analysis revealed the central role of Beclin 2 in autophagy regulation,uncovering its interactions with 39 newly identified proteins.Notably,the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1,which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results.Subsequently,in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1,promoted autophagy-dependent cell death,and inhibited proliferation and metastasis in MDA-MB-231 cells.Conclusions:This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy.These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.展开更多
BACKGROUND The programmed cell death protein 1 inhibitor pembrolizumab has become a key treatment for various cancers,including triple-negative breast cancer.However,it is associated with immune-related adverse events...BACKGROUND The programmed cell death protein 1 inhibitor pembrolizumab has become a key treatment for various cancers,including triple-negative breast cancer.However,it is associated with immune-related adverse events,including rare but serious neurological complications such as Guillain-Barrésyndrome(GBS).GBS is a potentially life-threatening autoimmune disorder characterized by muscle weakness and paralysis.We present a unique case of pembrolizumab-induced GBS to highlight the importance of recognizing this complication and managing it promptly in patients receiving immune checkpoint inhibitors.CASE SUMMARY A 69-year-old woman with a medical history of hypertension,anxiety,depression,and stage IIIB triple-negative breast cancer treated with pembrolizumab,carboplatin,and paclitaxel,presented to the emergency department with a 1-month history of tingling,lower extremity weakness,and shooting pain.Symptoms progressed to global weakness,ascending paralysis,and double vision.Neurological examination revealed significant lower extremity weakness and sensory deficits.Magnetic resonance imaging of the lumbar spine and cerebrospinal fluid analysis confirmed GBS.Initial treatment with intravenous immunoglobulin led to relapse,requiring additional intravenous immunoglobulin and high-dose glucocorticoids.The patient’s condition improved,pembrolizumab therapy was permanently discontinued,and she was discharged to a rehabilitation facility.CONCLUSION Pembrolizumab can induce GBS,necessitating early recognition,prompt diagnosis,and multidisciplinary management to prevent serious complications.展开更多
This article systematically reviews the application of biomimetic nanotechnology in targeted therapy for triple-negative breast cancer(TNBC).TNBC poses significant challenges for conventional treatments due to the lac...This article systematically reviews the application of biomimetic nanotechnology in targeted therapy for triple-negative breast cancer(TNBC).TNBC poses significant challenges for conventional treatments due to the lack of defined therapeutic targets,chemotherapy resistance,and a complex immunosuppressive microenvironment.Biomimetic nanotechnology,by mimicking the functional properties of biological structures(e.g.,cell membranes,exosomes),has significantly enhanced drug delivery efficiency,targeting precision,and anti-tumor immune responses.This review focuses on the design strategies of biomimetic nanocarriers(including cell membrane-coated nanoparticles,engineered exosomes,and biomimetic synthetic materials)and their innovative applications in TNBC therapy:(1)Targeted delivery systems that overcome tumor barriers and reduce systemic toxicity;(2)Photothermal therapy combined with immunomodulation for precise treatment and immune activation;(3)Tumor microenvironment regulation(e.g.,vascular normalization,pH neutralization,immunosuppression reversal).Studies demonstrate that biomimetic nanotechnology significantly improves TNBC treatment efficacy through multimodal synergistic mechanisms(e.g.,chemo-photothermal-immunotherapy).However,challenges such as scalable production,long-term safety,and personalized adaptation remain for clinical translation.Future research should integrate artificial intelligence for optimized design and dynamic imaging technologies to advance biomimetic nanomedicines toward clinical applications.展开更多
Immunotherapy of triple-negative breast cancer(TNBC)is significantly hindered by the immunosuppressive tumor microenvironment(TME).Notably,tumor-associated macrophages(TAMs),which constitute the predominant infiltrati...Immunotherapy of triple-negative breast cancer(TNBC)is significantly hindered by the immunosuppressive tumor microenvironment(TME).Notably,tumor-associated macrophages(TAMs),which constitute the predominant infiltrating immune cell type in TNBC,represent a critical target for“turning off”immunosuppressive TME.Despite numerous ongoing clinical trials,current strategies exhibit limited efficacy in overcoming immunosuppressive TME.Interestingly,regulation of son of sevenless 1(SOS1),which is overexpressed in TNBC patients,shows promising potential for TAM repolarization.Herein,we developed a biomimetic liposomal platform(CCM/Cil-lipo@TD),which integrates cilengitide(Cil)-functionalized breast cancer cell membranes(CCM)to co-deliver tetrandrine(TET)and low-dose docetaxel(DTX)for TNBC therapy.This system synergistically enhanced immunotherapy by coupling SOS1 blockade-driven TAM repolarization with immune cell death(ICD)-mediated dendritic cell(DC)maturation,thereby reshaping the highly immunosuppressive TME in TNBC.Critically,the low-density Cil-anchored,CCM-fused liposomes overcome the penetration limitations inherent to conventional CCM-based delivery systems,achieving deep intratumoral accumulation of therapeutic payloads.Mechanistically,the CCM/Cil-lipo@TD ensured that TET-mediated SOS1 inhibition in tumor cells efficiently polarized TAM2(protumor)toward TAM1(antitumor).Furthermore,SOS1 blockade synergized with low-dose DTX-induced ICD to remodel TME,as evidenced by sustained cytotoxic T-cell infiltration and suppression of regulatory T cells.The CCM/Cil-lipo@TD exerted superior tumor inhibition(82.9%)in 4T1 orthotopic models and effectively inhibited postoperative local recurrence and distant metastasis.Taken together,the Cil-engineered,cellmembrane-anchoring CCM/Cil-lipo@TD provides a promising approach for TNBC immunotherapy.展开更多
OBJECTIVE:To develop a safe and effective green therapy for triple-negative breast cancer,this study combines hydrogen-rich water with acupuncture point injection,and finds that it can prevent tumor growth and minimiz...OBJECTIVE:To develop a safe and effective green therapy for triple-negative breast cancer,this study combines hydrogen-rich water with acupuncture point injection,and finds that it can prevent tumor growth and minimize cancer metastasis.METHODS:After 21 d of hydrogen rich water injection treatment on 4T1(mouse breast cancer cells)xenograft mice,in order to systematically identify differentially expressed proteins in tumor samples between the model group and the Zusanli(ST36)group injected with hydrogen rich water at acupoints,with a focus on functional proteins or signaling pathways related to tumor occurrence and development,researchers conducted four-dimensional data independent acquisition(4D-DIA)proteomic analysis on tumor tissues.In order to further investigate the dynamic changes of metabolites after therapeutic intervention,researchers conducted liquid chromatography-tandem mass spectrometry untargeted metabolomics identification and analysis on mouse serum.The results of the joint proteomics–metabolomics analysis were validated using experimental methods such as immunofluorescence,Western blotting,and quantitative reverse transcription polymerase chain reaction detection.RESULTS:Injecting hydrogen-rich water into acupoints significantly inhibited tumor growth(P<0.05).4D-DIA proteomics and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses uncovered pathways such as T helper 1 cell(Th1)and T helper 2 cell(Th2)cell differentiation.The KEGG metabolic pathways identified in the metabolomics analysis included galactose metabolism along with fructose and mannose metabolism.Based on the combined proteomics and metabolomics analysis,the key pathways included the Ctype lectin receptor signaling pathway.The major cancerrelated differential proteins detected in Th1 and Th2 cell differentiation[interleukin 6 signal transducer,nuclear factor of activated T cells 4,recombinant mitogen activated protein kinase 10(MAPK10),and MAPK11]were upregulated after the injection of hydrogen-rich water into the Zusanli(ST36)acupoint,whereas Linker for activation of T cells(Lat),signal transducer and activator of transcription 1,and protein kinase C,theta were downregulated.CONCLUSION:The injection of hydrogen-rich water into the Zusanli(ST36)acupoint effectively inhibited the hyperplasia of 4T1 BC cells and enhanced their apoptosis,potentially exerting a therapeutic effect through multiple pathways and targeting various sites.展开更多
Background Preclinical studies demonstrate that exercise reduces tumor incidence and growth.Rapid release of extracellular vesicles(EVs)during exercise suggests their potential role as mediators of exercise-induced sy...Background Preclinical studies demonstrate that exercise reduces tumor incidence and growth.Rapid release of extracellular vesicles(EVs)during exercise suggests their potential role as mediators of exercise-induced systemic effects and physiological adaptation.This study investigated the impact of exercise-induced plasma EVs on tumor growth and immune tumor microenvironment in murine models of triple-negative breast cancer(TNBC):EO771(a C57BL/6-derived TNBC cell line)and 4T1(a BALB/c-derived TNBC cell line).Methods Size exclusion chromatography was used to isolate exercise-induced EVs from plasma of healthy female mice(BALB/c and C56BL/6,n=30 per strain)that underwent ten 30-min moderate-intensity treadmill running sessions over 2 weeks.Nanoparticle tracking analysis,Western blot,and electron microscopy confirmed the presence of EVs in the samples.Tumor-bearing mice(n=72 per strain)were administered with exercise-induced EVs before or/and after tumor implantation.Local and systemic immune responses were assessed using flow cytometry,enzyme-linked immunosorbent assay(ELISA),and quantitative polymerase chain reaction(qPCR).Results Administration of exercise-induced EVs,particularly before tumor implantation,significantly suppressed tumor growth and reduced tumor burden in both TNBC models.In EO771,endpoint tumor volumes were 278–330 mm^(3)in treated groups compared to 799 mm^(3)in untreated(p<0.0001),while in 4T1,treated groups showed volumes of 287–564 mm^(3)vs.696 mm^(3)in untreated(p=0.0002).Notable differences in tumor-infiltrating lymphoid and myeloid cell subpopulations indicated immunomodulatory effects of exercise-induced EVs,particularly in the 4T1 model,where their continuous administration significantly increased intratumoral cluster of differentiation 8(CD8)T lymphocyte proportion(5.77%vs.0.90%in untreated,p<0.0001).Similarly,in the EO771 model,exercise-induced EVs administered before tumor implantation led to a marked rise in intratumoral CD8 T lymphocytes(2.24%vs.1.08%in untreated,p=0.0181).Conclusion Our findings indicate that exercise-induced EV treatment elicits a pro-inflammatory antitumor immune response,suggesting a shift of immunologically cold TNBC tumors towards a more inflamed phenotype associated with better outcomes.Our study supports the further investigation of EVs as modulators of antitumor immunity and their potential utility in enhancing the efficacy of immunotherapy.展开更多
Most anti-tumor agents suffer from systemic non-specific distribution and low aggregation in tumors,which not only decreases the therapeutic efficacy,but also causes systemic toxic side effects in the treatments of tu...Most anti-tumor agents suffer from systemic non-specific distribution and low aggregation in tumors,which not only decreases the therapeutic efficacy,but also causes systemic toxic side effects in the treatments of tumors.In recent years,the rapid development of nanotechnology has brought new ideas for the application of anti-tumor drugs.Nanomedicines,such as liposomes and micelles,can improve drug targeting and prolong systemic circulation time to promote anti-tumor efficacy and reduce toxic side effects.However,conventional micelles bear the risk of instability and premature drug leaking in the blood circulation.We designed a reduction-responsive core-cross-linked micelle PTX@Fmoc-LA-PEG efficiently encapsulating Paclitaxel(PTX)viaπ-πstacking and hydrophobic interactions of Fmoc and PTX.Moreover,the micelle was further locked based on the cross-linking properties of the disulfide bonds formed by lipoic acid(LA).As expected,the core-cross-linked micelles PTX@Fmoc-LA-PEG remained stable in normal physiological environments,while restoring the normal drug release rate of micelles under the highly reducing environment due to LA unlocking.The blank micelles(Fmoc-LA-PEG)exhibited excellent biocompatibility,while the drug-loaded micelles(PTX@Fmoc-LA-PEG)displayed a remarkable anti-tumor effect in vitro and in vivo experiments.These results suggested that core-cross-linked micelles PTX@FmocLA-PEG have great potential to improve the targeting and stability of anti-tumor drugs.展开更多
The heterogeneity of triple-negative breast cancer(TNBC)has spurred the exploration of precision therapies based on molecular subtypes,with the androgen receptor(AR)-positive subtype emerging as a potential therapeuti...The heterogeneity of triple-negative breast cancer(TNBC)has spurred the exploration of precision therapies based on molecular subtypes,with the androgen receptor(AR)-positive subtype emerging as a potential therapeutic target.The treatment of AR-positive TNBC relies primarily on androgen receptor antagonists,such as enobosarm,bicalutamide,and enzalutamide.To enhance efficacy,researchers are investigating combination therapies that integrate anti-androgen agents with chemotherapy,immunotherapy,or PARP inhibitors.Additionally,studies have revealed that the AR signaling pathway regulates the tumor microenvironment,and AR inhibition may potentiate the efficacy of immune checkpoint inhibitors.However,anti-AR therapies face significant limitations and challenges due to multifaceted factors,necessitating further resolution.With continued advancements,AR-targeted therapy holds promise as a critical component of personalized treatment strategies for TNBC.展开更多
Objective:While immunotherapy holds great potential for triple-negative breast cancer(TNBC),the lack of non-invasive biomarkers to identify beneficiaries limits the application.Methods:Paired baseline,on-treatment,and...Objective:While immunotherapy holds great potential for triple-negative breast cancer(TNBC),the lack of non-invasive biomarkers to identify beneficiaries limits the application.Methods:Paired baseline,on-treatment,and post-treatment plasma samples were collected from 195 TNBC patients receiving anti-PD-1 immunotherapy in this retrospective study conducted at the Fudan University Shanghai Cancer Center(FUSCC)for sequential high-precision proteomic profiling.Results:ARG1,NOS3,and CD28 were identified as plasma proteins significantly associated with the response to immunotherapy in neoadjuvant settings or in advanced stages of TNBC.Matched single-cell RNA sequencing data were incorporated to correlate peripheral plasma with the tumor microenvironment.Furthermore,the Plasma Immuno Prediction Score was developed to demonstrate significant predictive power for evaluating the efficacy and prognosis of patients undergoing neoadjuvant immunotherapy.Conclusions:The results underscore the importance of systemic immunity in the immunotherapy response and support the use of plasma protein profiles as a feasible tool for enhancing personalized management of immunotherapy in breast cancer.展开更多
Objective:Triple-negative breast cancer(TNBC)remains a major therapeutic challenge with limited treatment options and poor prognosis.This study aimed to investigate the synergistic anticancer effects of doxorubicin(DO...Objective:Triple-negative breast cancer(TNBC)remains a major therapeutic challenge with limited treatment options and poor prognosis.This study aimed to investigate the synergistic anticancer effects of doxorubicin(DOX)combined with Viscum album L.var.coloratum agglutinin(VCA)and to elucidate the underlying molecular mechanisms in TNBC cells.Methods:This study evaluated the synergistic effects and mechanisms of doxorubicin(DOX)and Viscum album L.var.coloratum agglutinin(VCA)combination in MDA-MB231 TNBC cells.Cell viability,oxidative stress markers,apoptosis-related proteins,cell migration,and proliferative recovery were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay,superoxide dismutase(SOD)and nitric oxide(NO)assays,Western blotting,wound healing assay,and Muse^(TM)cell analyzer,respectively.Results:The DOXVCA combination demonstrated strong synergistic cytotoxicity with Bliss Independence scores of+8.9% to+33.4% at therapeutic concentrations(0.01-50 ng/mL,p=0.032)and remarkable dose reduction indices of>3000-fold for DOX and>16.7-fold for VCA.This synergistic effect was mediated through multiple mechanisms:enhanced oxidative stress modulation(48% increase in SOD-like activity,p=0.0003,and 94% increase in NO production,p=0.0002,at 50 ng/mL combination compared to control),augmented apoptotic responses(4.8-fold increase in cleaved caspase-3/caspase-3 ratio,p=0.0001,and 91% reduction in procaspase-9 levels,p=0.00008,at 48 h compared to control),significant inhibition of cell migration(85.8% remaining wound area at 48 h,p=0.0004 vs.control),and severely impaired proliferative recovery(98.9% reduction in cell viability at 72 h post-treatment,p=0.0001 vs.untreatedcontrol).Conclusion:The DOX-VCA combination demonstrates potent synergistic effects through multiple mechanisms,warranting further investigation as a potential dose-reducing strategy for TNBC treatment.展开更多
[Objectives]To investigate the anti-tumor molecular mechanism of acetylenic phenols against triple-negative breast cancer(TNBC)using network pharmacology and molecular docking approaches.[Methods]Based on team s previ...[Objectives]To investigate the anti-tumor molecular mechanism of acetylenic phenols against triple-negative breast cancer(TNBC)using network pharmacology and molecular docking approaches.[Methods]Based on team s previous in vitro activity screening,the most active acetylenic phenols were selected for further analysis.Genes associated with triple-negative breast cancer(TNBC)were retrieved from the GAD and OMIM databases.Using Cytoscape software,a compound-target-pathway interaction network was constructed to visualize the relationships between the acetylenic phenols,their potential targets,and related pathways.Functional enrichment analysis of GO terms and KEGG pathways was performed using the DAVID database to identify key signaling mechanisms.Furthermore,molecular docking was conducted to evaluate the binding interactions between the acetylenic phenols and the potential core targets.[Results]Acetylenic phenols exhibit potential anticancer effects by modulating multiple signaling pathways,including the PI3K-Akt pathway,cell cycle pathway,and breast cancer pathway,which are closely associated with the pathophysiological processes of triple-negative breast cancer(TNBC)such as cell proliferation,apoptosis,and cell cycle regulation.Molecular docking results indicated that acetylenic phenols bind effectively to their targets via hydrogen bonding,hydrophobic interactions,andπ-stacking,indicating strong binding affinity.[Conclusions]Acetylenic phenols exert anti-TNBC effects by modulating key targets,including EGFR,RAF1,ESR1,CHEK1,and CDC25C,and influencing associated signaling pathways.These findings reveal the molecular mechanism underlying their anti-TNBC activity and provide a theoretical foundation for the potential application of acetylenic phenols in TNBC treatment.展开更多
基金supported by the Natural Science Foundation of Jilin Province(No.SKL202302002).
文摘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.
文摘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.
基金supported by the Regional Innovation System&Education(RISE)program through the Jeollanamdo RISE center,funded by the Ministry of Education(MOE)and the Jeollanamdo,Republic of Korea(2025-RISE-14-003).
文摘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.
基金supported by the Jilin Province Health Science and Technology Ability Improvement Project(2023JL057).
文摘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.
文摘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.
基金supported by Shandong Provincial Natural Science Foundation(no.ZR2020MH319).
文摘Triple-negative breast cancer(TNBC)is currently the most heterogeneous and aggressive breast cancer type.It has a high recurrence rate,poor clinical prospects,and lack of predictive markers and potential treatment options.Dysregulated microRNAs(miRNAs)are involved in various cellular processes in TNBC.Moreover,variations in the miRNA levels in TNBC may act as a dependable indicator for predicting the effectiveness and specificity of treatments.Currently,the application of miRNAs for breast cancer therapy is primarily in the preclinical stage,with a focus on identifying highly specific and sensitive miRNAs that could offer new possibilities for early diagnosis,clinical treat-ment,and prognostic monitoring of TNBC.
基金supported by grants from the Medical Engineering Jiont Fund of the Fudan University(No.IDH2310117)。
文摘Objective:Triple-negative breast cancer(TNBC)is a highly aggressive subtype that lacks targeted therapies,leading to a poorer prognosis.However,some patients achieve long-term recurrence-free survival(RFS),offering valuable insights into tumor biology and potential treatment strategies.Methods:We conducted a comprehensive multi-omics analysis of 132 patients with American Joint Committee on Cancer(AJCC)stage III TNBC,comprising 36 long-term survivors(RFS≥8 years),62 moderate-term survivors(RFS:3-8 years),and 34 short-term survivors(RFS<3 years).Analyses investigated clinicopathological factors,whole-exome sequencing,germline mutations,copy number alterations(CNAs),RNA sequences,and metabolomic profiles.Results:Long-term survivors exhibited fewer metastatic regional lymph nodes,along with tumors showing reduced stromal fibrosis and lower Ki67 index.Molecularly,these tumors exhibited multiple alterations in genes related to homologous recombination repair,with higher frequencies of germline mutations and somatic CNAs.Additionally,tumors from long-term survivors demonstrated significant downregulation of the RTK-RAS signaling pathway.Metabolomic profiling revealed decreased levels of lipids and carbohydrate,particularly those involved in glycerophospholipid,fructose,and mannose metabolism,in long-term survival group.Multivariate Cox analysis identified fibrosis[hazard ratio(HR):12.70,95%confidence interval(95%CI):2.19-73.54,P=0.005]and RAC1copy number loss/deletion(HR:0.22,95%CI:0.06-0.83,P=0.026)as independent predictors of RFS.Higher fructose/mannose metabolism was associated with worse overall survival(HR:1.30,95%CI:1.01-1.68,P=0.045).Our findings emphasize the association between biological determinants and prolonged survival in patients with TNBC.Conclusions:Our study systematically identified the key molecular and metabolic features associated with prolonged survival in AJCC stage III TNBC,suggesting potential therapeutic targets to improve patient outcomes.
基金supported by the National Nature Science Foundation of China(NO.82260699)the Science and Technology Leading Talents of Ningxia(NO.2022GKLRLX011)the West Light Foundation of The Chinese Academy of Sciences(the Science and Technology Department of Ningxia,Department of Science and Technology Cooperation[2021]NO.2).
文摘Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer(TNBC)therapy.However,the ferroptosis accompanied with down-regulation of glutathione peroxidase 4(GPX4)lead to CD36-mediated tumor-infiltrating CD8^(+)T cells uptaking fatty acids,resulting in the negative action on immunotherapeutic efficacy.Herein,the albumin nanoparticles,abbreviated as LHS NPs,were designed by co-assembly of hemin,linoleic acid-cystamine,and a CD36 inhibitor sulfosuccinimide oleate,to bi-directionally manipulated ferroptosis in tumor and CD8^(+)T cells for TNBC therapy.LHS NPs exerted more efficient reactive oxygen species generation,glutathione depletion and malondialdehyde production by the combinatory strategy of classical and non-classical ferroptosis modes,which amplified the positive action on ferroptosis in tumor cells.Meanwhile,LHS manipulated the negative action of ferroptosis by inhibiting the CD36 mediated-lipid peroxidation in CD8^(+)T cells,thereby activating the immunotherapeutic efficacy with the improvements on induction of immunogenic cell death,proliferation of CD4+CD8^(+)T cells and natural killer cells,alleviation immunosuppressive regulatory T cells and myeloid-derived suppressor cells,and repolarization of the M2-to M1-phenotype tumor-associated macrophages.Thus,LHS NPs demonstrated an improved antitumor efficacy in suppressing the tumor growth and lungmetastasis of 4T1-tumormice.Our work gives novel insights for the bi-directionally manipulating ferroptosis in tumor and CD8^(+)T cells on TNBC chemoimmunotherapy.
基金the Xuzhou Science and Technology Bureau,No.KC23186,Jiangsu Provincial Key Laboratory of New Drug Research and Clinical Pharmacy Project(No.XZSYSKF2023013)Key Medical Disciplines of Jiangsu Province’s 14th Five-Year Plan(ZDXK202237).
文摘Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side effects.Astragalus polysaccharide(APS)is one of the active components extracted from Astragalus membranaceus and has gained attention for its various biological properties.This research is aimed to evaluate the effectiveness of a combination of APS and DDP on TNBC and explore the potential mechanisms.Methods:The efficacy and mechanisms of single or combined treatment were evaluated using Cell Counting Kit-8(CCK8)assay,Annexin V-fluorescein isothiocyanate(FITC)/propidium iodide(PI)staining,wound healing assay,trans-well invasion/migration assay,hematoxylin-eosin(HE)staining,immunohistochemical(IHC)staining,Western Blot(WB)analysis,and fluorescence-activated cell sorting(FACS).An orthotopic model of TNBC was used to assess the in vivo treatment efficacy of single or combination treatment.Results:APS significantly enhanced the anti-proliferative,anti-migratory,and anti-invasive effects of DDP on TNBC cells.The combination of APS and DDP downregulated anti-apoptotic genes(Bcl2 and Bcl-xL)while upregulating pro-apoptotic genes(Puma,Cle-Caspase3,Cle-PARP),leading to enhanced apoptosis.This combination treatment increased E-cadherin levels,decreased Vimentin,Snail,Slug,and Twist levels,and effectively suppressed epithelial-mesenchymal transition(EMT)-associated cell invasion.In the orthotopic model of TNBC,a synergistic reduction in tumor growth was observed in mice treated with APS and DDP.Additionally,the combination of APS and DDP induced the infiltration of CD8+T lymphocytes into the tumor immune microenvironment.Conclusion:The combination of APS and DDP exhibits more potent tumor inhibition and anti-tumor immunity than either agent alone,representing a novel approach to enhance therapeutic efficacy without increasing the side effects of DDP.
基金the National Natural Science Foundation of China(Nos.22307009,82374155,82073997,82104376)the Sichuan Science and Technology Program(Nos.2023NSFSC1108,2024NSFTD0023)+1 种基金the Postdoctoral Research Project of Sichuan Provincethe Xinglin Scholar Research Promotion Project of Chengdu University of TCM.
文摘Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autophagy is an important process for maintaining cellular homeostasis,and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors.In contrast to targeting protein activity,intervention with proteinprotein interaction(PPI)can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.Methods:Here,we employed Naive Bayes,Decision Tree,and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC,aiming to uncover novel therapeutic targets.Meanwhile,the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay,and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection.Colony formation,cellular immunofluorescence,cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.Results:By developing three PPI classification models and analyzing over 13,000 datasets,we identified 3733 previously unknown autophagy-related PPIs.Our network analysis revealed the central role of Beclin 2 in autophagy regulation,uncovering its interactions with 39 newly identified proteins.Notably,the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1,which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results.Subsequently,in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1,promoted autophagy-dependent cell death,and inhibited proliferation and metastasis in MDA-MB-231 cells.Conclusions:This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy.These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.
文摘BACKGROUND The programmed cell death protein 1 inhibitor pembrolizumab has become a key treatment for various cancers,including triple-negative breast cancer.However,it is associated with immune-related adverse events,including rare but serious neurological complications such as Guillain-Barrésyndrome(GBS).GBS is a potentially life-threatening autoimmune disorder characterized by muscle weakness and paralysis.We present a unique case of pembrolizumab-induced GBS to highlight the importance of recognizing this complication and managing it promptly in patients receiving immune checkpoint inhibitors.CASE SUMMARY A 69-year-old woman with a medical history of hypertension,anxiety,depression,and stage IIIB triple-negative breast cancer treated with pembrolizumab,carboplatin,and paclitaxel,presented to the emergency department with a 1-month history of tingling,lower extremity weakness,and shooting pain.Symptoms progressed to global weakness,ascending paralysis,and double vision.Neurological examination revealed significant lower extremity weakness and sensory deficits.Magnetic resonance imaging of the lumbar spine and cerebrospinal fluid analysis confirmed GBS.Initial treatment with intravenous immunoglobulin led to relapse,requiring additional intravenous immunoglobulin and high-dose glucocorticoids.The patient’s condition improved,pembrolizumab therapy was permanently discontinued,and she was discharged to a rehabilitation facility.CONCLUSION Pembrolizumab can induce GBS,necessitating early recognition,prompt diagnosis,and multidisciplinary management to prevent serious complications.
文摘This article systematically reviews the application of biomimetic nanotechnology in targeted therapy for triple-negative breast cancer(TNBC).TNBC poses significant challenges for conventional treatments due to the lack of defined therapeutic targets,chemotherapy resistance,and a complex immunosuppressive microenvironment.Biomimetic nanotechnology,by mimicking the functional properties of biological structures(e.g.,cell membranes,exosomes),has significantly enhanced drug delivery efficiency,targeting precision,and anti-tumor immune responses.This review focuses on the design strategies of biomimetic nanocarriers(including cell membrane-coated nanoparticles,engineered exosomes,and biomimetic synthetic materials)and their innovative applications in TNBC therapy:(1)Targeted delivery systems that overcome tumor barriers and reduce systemic toxicity;(2)Photothermal therapy combined with immunomodulation for precise treatment and immune activation;(3)Tumor microenvironment regulation(e.g.,vascular normalization,pH neutralization,immunosuppression reversal).Studies demonstrate that biomimetic nanotechnology significantly improves TNBC treatment efficacy through multimodal synergistic mechanisms(e.g.,chemo-photothermal-immunotherapy).However,challenges such as scalable production,long-term safety,and personalized adaptation remain for clinical translation.Future research should integrate artificial intelligence for optimized design and dynamic imaging technologies to advance biomimetic nanomedicines toward clinical applications.
基金the National Facility for Protein Science in Shanghai(NFPS),Shanghai Advanced Research Institute,Chinese Academy of Science,China for providing the Electron Microscopy System technical support and assistance in data collection and analysisfunded by“Shuguang Program”supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission(22SG41)the combination of the medical care and health project of the Shanghai University of Traditional Chinese Medicine(YYKC-2021-01-008).
文摘Immunotherapy of triple-negative breast cancer(TNBC)is significantly hindered by the immunosuppressive tumor microenvironment(TME).Notably,tumor-associated macrophages(TAMs),which constitute the predominant infiltrating immune cell type in TNBC,represent a critical target for“turning off”immunosuppressive TME.Despite numerous ongoing clinical trials,current strategies exhibit limited efficacy in overcoming immunosuppressive TME.Interestingly,regulation of son of sevenless 1(SOS1),which is overexpressed in TNBC patients,shows promising potential for TAM repolarization.Herein,we developed a biomimetic liposomal platform(CCM/Cil-lipo@TD),which integrates cilengitide(Cil)-functionalized breast cancer cell membranes(CCM)to co-deliver tetrandrine(TET)and low-dose docetaxel(DTX)for TNBC therapy.This system synergistically enhanced immunotherapy by coupling SOS1 blockade-driven TAM repolarization with immune cell death(ICD)-mediated dendritic cell(DC)maturation,thereby reshaping the highly immunosuppressive TME in TNBC.Critically,the low-density Cil-anchored,CCM-fused liposomes overcome the penetration limitations inherent to conventional CCM-based delivery systems,achieving deep intratumoral accumulation of therapeutic payloads.Mechanistically,the CCM/Cil-lipo@TD ensured that TET-mediated SOS1 inhibition in tumor cells efficiently polarized TAM2(protumor)toward TAM1(antitumor).Furthermore,SOS1 blockade synergized with low-dose DTX-induced ICD to remodel TME,as evidenced by sustained cytotoxic T-cell infiltration and suppression of regulatory T cells.The CCM/Cil-lipo@TD exerted superior tumor inhibition(82.9%)in 4T1 orthotopic models and effectively inhibited postoperative local recurrence and distant metastasis.Taken together,the Cil-engineered,cellmembrane-anchoring CCM/Cil-lipo@TD provides a promising approach for TNBC immunotherapy.
基金the National Natural Science Foundation of China:Exploring the Advantages of Micro-needle System Therapy for Specific Diseases and the Patterns of Acupoint Selection through Data Mining Techniques(No.81473773)Key Project of Hebei Provincial Education Department:Exploring the Molecular Mechanism behind How Hydrogen Mitigates the Aging of Vascular Endothelial Cells Induced by Chronic Intermittent Hypoxia,Utilizing the Keap1-Nuclear factor erythroid 2-related factor 2 Signaling Pathway(No.ZD2020142)Hebei University of Traditional Chinese Medicine 2024 Graduate Student Innovation Funding Project:Study on the Inhibitory Effect and Mechanism of Hydrogen-rich Water Acupoint Injection on Tumors in Mice with Triple-negative Breast Cancer(No.CXZZBS2024154)。
文摘OBJECTIVE:To develop a safe and effective green therapy for triple-negative breast cancer,this study combines hydrogen-rich water with acupuncture point injection,and finds that it can prevent tumor growth and minimize cancer metastasis.METHODS:After 21 d of hydrogen rich water injection treatment on 4T1(mouse breast cancer cells)xenograft mice,in order to systematically identify differentially expressed proteins in tumor samples between the model group and the Zusanli(ST36)group injected with hydrogen rich water at acupoints,with a focus on functional proteins or signaling pathways related to tumor occurrence and development,researchers conducted four-dimensional data independent acquisition(4D-DIA)proteomic analysis on tumor tissues.In order to further investigate the dynamic changes of metabolites after therapeutic intervention,researchers conducted liquid chromatography-tandem mass spectrometry untargeted metabolomics identification and analysis on mouse serum.The results of the joint proteomics–metabolomics analysis were validated using experimental methods such as immunofluorescence,Western blotting,and quantitative reverse transcription polymerase chain reaction detection.RESULTS:Injecting hydrogen-rich water into acupoints significantly inhibited tumor growth(P<0.05).4D-DIA proteomics and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses uncovered pathways such as T helper 1 cell(Th1)and T helper 2 cell(Th2)cell differentiation.The KEGG metabolic pathways identified in the metabolomics analysis included galactose metabolism along with fructose and mannose metabolism.Based on the combined proteomics and metabolomics analysis,the key pathways included the Ctype lectin receptor signaling pathway.The major cancerrelated differential proteins detected in Th1 and Th2 cell differentiation[interleukin 6 signal transducer,nuclear factor of activated T cells 4,recombinant mitogen activated protein kinase 10(MAPK10),and MAPK11]were upregulated after the injection of hydrogen-rich water into the Zusanli(ST36)acupoint,whereas Linker for activation of T cells(Lat),signal transducer and activator of transcription 1,and protein kinase C,theta were downregulated.CONCLUSION:The injection of hydrogen-rich water into the Zusanli(ST36)acupoint effectively inhibited the hyperplasia of 4T1 BC cells and enhanced their apoptosis,potentially exerting a therapeutic effect through multiple pathways and targeting various sites.
基金funded by the Europe Economic Area(EEA)and Norway Grants 2014-2021,Grant No.EEA-RESEARCH-164 for AM,ALl,and ALi.
文摘Background Preclinical studies demonstrate that exercise reduces tumor incidence and growth.Rapid release of extracellular vesicles(EVs)during exercise suggests their potential role as mediators of exercise-induced systemic effects and physiological adaptation.This study investigated the impact of exercise-induced plasma EVs on tumor growth and immune tumor microenvironment in murine models of triple-negative breast cancer(TNBC):EO771(a C57BL/6-derived TNBC cell line)and 4T1(a BALB/c-derived TNBC cell line).Methods Size exclusion chromatography was used to isolate exercise-induced EVs from plasma of healthy female mice(BALB/c and C56BL/6,n=30 per strain)that underwent ten 30-min moderate-intensity treadmill running sessions over 2 weeks.Nanoparticle tracking analysis,Western blot,and electron microscopy confirmed the presence of EVs in the samples.Tumor-bearing mice(n=72 per strain)were administered with exercise-induced EVs before or/and after tumor implantation.Local and systemic immune responses were assessed using flow cytometry,enzyme-linked immunosorbent assay(ELISA),and quantitative polymerase chain reaction(qPCR).Results Administration of exercise-induced EVs,particularly before tumor implantation,significantly suppressed tumor growth and reduced tumor burden in both TNBC models.In EO771,endpoint tumor volumes were 278–330 mm^(3)in treated groups compared to 799 mm^(3)in untreated(p<0.0001),while in 4T1,treated groups showed volumes of 287–564 mm^(3)vs.696 mm^(3)in untreated(p=0.0002).Notable differences in tumor-infiltrating lymphoid and myeloid cell subpopulations indicated immunomodulatory effects of exercise-induced EVs,particularly in the 4T1 model,where their continuous administration significantly increased intratumoral cluster of differentiation 8(CD8)T lymphocyte proportion(5.77%vs.0.90%in untreated,p<0.0001).Similarly,in the EO771 model,exercise-induced EVs administered before tumor implantation led to a marked rise in intratumoral CD8 T lymphocytes(2.24%vs.1.08%in untreated,p=0.0181).Conclusion Our findings indicate that exercise-induced EV treatment elicits a pro-inflammatory antitumor immune response,suggesting a shift of immunologically cold TNBC tumors towards a more inflamed phenotype associated with better outcomes.Our study supports the further investigation of EVs as modulators of antitumor immunity and their potential utility in enhancing the efficacy of immunotherapy.
基金supported by CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-026)the Postdoctoral Fellowship Program of CPSF(No.GZC20230313)。
文摘Most anti-tumor agents suffer from systemic non-specific distribution and low aggregation in tumors,which not only decreases the therapeutic efficacy,but also causes systemic toxic side effects in the treatments of tumors.In recent years,the rapid development of nanotechnology has brought new ideas for the application of anti-tumor drugs.Nanomedicines,such as liposomes and micelles,can improve drug targeting and prolong systemic circulation time to promote anti-tumor efficacy and reduce toxic side effects.However,conventional micelles bear the risk of instability and premature drug leaking in the blood circulation.We designed a reduction-responsive core-cross-linked micelle PTX@Fmoc-LA-PEG efficiently encapsulating Paclitaxel(PTX)viaπ-πstacking and hydrophobic interactions of Fmoc and PTX.Moreover,the micelle was further locked based on the cross-linking properties of the disulfide bonds formed by lipoic acid(LA).As expected,the core-cross-linked micelles PTX@Fmoc-LA-PEG remained stable in normal physiological environments,while restoring the normal drug release rate of micelles under the highly reducing environment due to LA unlocking.The blank micelles(Fmoc-LA-PEG)exhibited excellent biocompatibility,while the drug-loaded micelles(PTX@Fmoc-LA-PEG)displayed a remarkable anti-tumor effect in vitro and in vivo experiments.These results suggested that core-cross-linked micelles PTX@FmocLA-PEG have great potential to improve the targeting and stability of anti-tumor drugs.
文摘The heterogeneity of triple-negative breast cancer(TNBC)has spurred the exploration of precision therapies based on molecular subtypes,with the androgen receptor(AR)-positive subtype emerging as a potential therapeutic target.The treatment of AR-positive TNBC relies primarily on androgen receptor antagonists,such as enobosarm,bicalutamide,and enzalutamide.To enhance efficacy,researchers are investigating combination therapies that integrate anti-androgen agents with chemotherapy,immunotherapy,or PARP inhibitors.Additionally,studies have revealed that the AR signaling pathway regulates the tumor microenvironment,and AR inhibition may potentiate the efficacy of immune checkpoint inhibitors.However,anti-AR therapies face significant limitations and challenges due to multifaceted factors,necessitating further resolution.With continued advancements,AR-targeted therapy holds promise as a critical component of personalized treatment strategies for TNBC.
基金supported by the National Key Research and Development Project of China(Grant No.2021YFF1201300 and 2021YFF1201302)the Shanghai Committee of Science and Technology(Grant No.24DX2800100)the Institutional Projects of SIBPT(Grant No.YZ2024-07)。
文摘Objective:While immunotherapy holds great potential for triple-negative breast cancer(TNBC),the lack of non-invasive biomarkers to identify beneficiaries limits the application.Methods:Paired baseline,on-treatment,and post-treatment plasma samples were collected from 195 TNBC patients receiving anti-PD-1 immunotherapy in this retrospective study conducted at the Fudan University Shanghai Cancer Center(FUSCC)for sequential high-precision proteomic profiling.Results:ARG1,NOS3,and CD28 were identified as plasma proteins significantly associated with the response to immunotherapy in neoadjuvant settings or in advanced stages of TNBC.Matched single-cell RNA sequencing data were incorporated to correlate peripheral plasma with the tumor microenvironment.Furthermore,the Plasma Immuno Prediction Score was developed to demonstrate significant predictive power for evaluating the efficacy and prognosis of patients undergoing neoadjuvant immunotherapy.Conclusions:The results underscore the importance of systemic immunity in the immunotherapy response and support the use of plasma protein profiles as a feasible tool for enhancing personalized management of immunotherapy in breast cancer.
文摘Objective:Triple-negative breast cancer(TNBC)remains a major therapeutic challenge with limited treatment options and poor prognosis.This study aimed to investigate the synergistic anticancer effects of doxorubicin(DOX)combined with Viscum album L.var.coloratum agglutinin(VCA)and to elucidate the underlying molecular mechanisms in TNBC cells.Methods:This study evaluated the synergistic effects and mechanisms of doxorubicin(DOX)and Viscum album L.var.coloratum agglutinin(VCA)combination in MDA-MB231 TNBC cells.Cell viability,oxidative stress markers,apoptosis-related proteins,cell migration,and proliferative recovery were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay,superoxide dismutase(SOD)and nitric oxide(NO)assays,Western blotting,wound healing assay,and Muse^(TM)cell analyzer,respectively.Results:The DOXVCA combination demonstrated strong synergistic cytotoxicity with Bliss Independence scores of+8.9% to+33.4% at therapeutic concentrations(0.01-50 ng/mL,p=0.032)and remarkable dose reduction indices of>3000-fold for DOX and>16.7-fold for VCA.This synergistic effect was mediated through multiple mechanisms:enhanced oxidative stress modulation(48% increase in SOD-like activity,p=0.0003,and 94% increase in NO production,p=0.0002,at 50 ng/mL combination compared to control),augmented apoptotic responses(4.8-fold increase in cleaved caspase-3/caspase-3 ratio,p=0.0001,and 91% reduction in procaspase-9 levels,p=0.00008,at 48 h compared to control),significant inhibition of cell migration(85.8% remaining wound area at 48 h,p=0.0004 vs.control),and severely impaired proliferative recovery(98.9% reduction in cell viability at 72 h post-treatment,p=0.0001 vs.untreatedcontrol).Conclusion:The DOX-VCA combination demonstrates potent synergistic effects through multiple mechanisms,warranting further investigation as a potential dose-reducing strategy for TNBC treatment.
基金Supported by General Program of Natural Science Foundation of Sichuan Province(2024NSFSC0706)Program of Sichuan Administration of Traditional Chinese Medicine(25MSZX326)+1 种基金Research Initiation Fund for High-level Talents of Sichuan College of Traditional Chinese Medicine(24ZRBS05)School-level Project of Sichuan College of Traditional Chinese Medicine(24SD02).
文摘[Objectives]To investigate the anti-tumor molecular mechanism of acetylenic phenols against triple-negative breast cancer(TNBC)using network pharmacology and molecular docking approaches.[Methods]Based on team s previous in vitro activity screening,the most active acetylenic phenols were selected for further analysis.Genes associated with triple-negative breast cancer(TNBC)were retrieved from the GAD and OMIM databases.Using Cytoscape software,a compound-target-pathway interaction network was constructed to visualize the relationships between the acetylenic phenols,their potential targets,and related pathways.Functional enrichment analysis of GO terms and KEGG pathways was performed using the DAVID database to identify key signaling mechanisms.Furthermore,molecular docking was conducted to evaluate the binding interactions between the acetylenic phenols and the potential core targets.[Results]Acetylenic phenols exhibit potential anticancer effects by modulating multiple signaling pathways,including the PI3K-Akt pathway,cell cycle pathway,and breast cancer pathway,which are closely associated with the pathophysiological processes of triple-negative breast cancer(TNBC)such as cell proliferation,apoptosis,and cell cycle regulation.Molecular docking results indicated that acetylenic phenols bind effectively to their targets via hydrogen bonding,hydrophobic interactions,andπ-stacking,indicating strong binding affinity.[Conclusions]Acetylenic phenols exert anti-TNBC effects by modulating key targets,including EGFR,RAF1,ESR1,CHEK1,and CDC25C,and influencing associated signaling pathways.These findings reveal the molecular mechanism underlying their anti-TNBC activity and provide a theoretical foundation for the potential application of acetylenic phenols in TNBC treatment.
