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
To address the issue of PD-1 inhibitor resistance driven by the immunosuppressive tumor microenvironment in triple-negative breast cancer(TNBC),we constructed activated platelet membrane-derived vesicles for targeted ...To address the issue of PD-1 inhibitor resistance driven by the immunosuppressive tumor microenvironment in triple-negative breast cancer(TNBC),we constructed activated platelet membrane-derived vesicles for targeted delivery of hemopexin(HPX)small interfering RNA(siRNA)(APP@siHPX),which effectively reduced the extracellular transport of heme and inhibited heme-mediated thrombospondin-1(TSP-1)release,leading to decreased tumor-associated macrophage(TAM)recruitment and reprogramming of TAMs from the M2 phenotype to the M1 phenotype.Consequently,combining APP@siHPX with PD-1 inhibitors synergistically alleviates T-cell immunosuppression and increases CD8^(+)T-cell activity,resulting in significant tumor growth inhibition.In summary,our results demonstrate that targeting the HPX-heme-TSP-1 axis via APP@siHPX represents a promising strategy for enhancing the efficacy of immune checkpoint inhibitors 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
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
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
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
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
Objectives:Triple-negative breast cancer(TNBC)presents a major treatment challenge due to its aggressive behavior.The dysfunction of the Golgi apparatus(GA)contributes to the development of various cancers.This study ...Objectives:Triple-negative breast cancer(TNBC)presents a major treatment challenge due to its aggressive behavior.The dysfunction of the Golgi apparatus(GA)contributes to the development of various cancers.This study aimed to utilize GA-related genes(GARGs)to forecast the prognosis and immune profile of TNBC.Methods:The data were downloaded from The Cancer Genome Atlas(TCGA)database,including 175 TNBC and 99 healthy samples.The differentially expressed GARGs(DEGARGs)were analyzed using the TCGA biolinks package.The patients with TNBC were classified into two clusters utilizing the ConsensusClusterPlus package according to prognosis-related DEGARGs,followed by comparing the differences in prognosis and immune infiltration between the two clusters.Next,LASSO and stepwise Cox regression were applied to establish a GARGs signature to forecast the TNBC prognosis.The association of the GARGs signature with immune infiltrates and drug sensitivity was further explored.Results:In total,430 DEGARGs were identified between TNBC and healthy samples,among which 20 were related to TNBC prognosis.Two GARG-related molecular clusters associated with different survival times and immune heterogeneity were identified.A risk model for TNBC was established based on six GARGs,and the high-risk(HR)group exhibited a poor prognosis.The HR group demonstrated a distinctly high M2 macrophage infiltration and low M1 macrophage infiltration,which contributed to an immunosuppressive tumor microenvironment and thus led to poor prognosis of the HR group.Immune dysfunction scores and programmed cell death ligand 1(PD-L1)expression were substantially elevated in the HR group.The HR group showed increased sensitivity to anticancer drugs,such as cisplatin.Conclusion:Our findings suggest that GARGs are involved in the pathogenesis of TNBC and provide new insights into prognostic prediction.The identified clusters and GARGs signatures have the potential to guide individualized therapy.展开更多
The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer(TNBC).Recent research ...The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer(TNBC).Recent research indicates the aberrant expression of diverse tyrosine kinases(TKs)within this cancer,contributing significantly to tumor cell proliferation,survival,invasion,and migration.The contemporary paradigm shift towards precision medicine has highlighted TKs and their receptors as promising targets for pharmacotherapy against a range of malignancies,given their pivotal roles in tumor initiation,progression,and advancement.Intensive investigations have focused on various monoclonal antibodies(mAbs)and small molecule inhibitors that specifically target proteins such as epidermal growth factor receptor(EGFR),vascular endothelial growth factor(VEGF),vascular endothelial growth factor receptor(VEGFR),cellular mesenchymal-epithelial transition factor(c-MET),human epidermal growth factor receptor 2(HER2),among others,for combating TNBC.These agents have been studied both in monotherapy and in combination with other chemotherapeutic agents.Despite these advances,a substantial terrain of unexplored potential lies within the realm of TK-targeted therapeutics,which hold promise in reshaping the therapeutic landscape.This review summarizes the various TK-targeted therapeutics that have undergone scrutiny as potential therapeutic interventions for TNBC,dissecting the outcomes and revelations stemming from diverse clinical investigations.A key conclusion from the umbrella clinical trials evidences the necessity for in-depth molecular characterization of TNBC for the maximum efficiency of TK-targeted therapeutics,either as standalone treatments or a combination.Moreover,our observation highlights that the outcomes of TK-targeted therapeutics in TNBC are substantially influenced by the diversity of the patient cohort,emphasizing the prioritization of individual patient genetic/molecular profiles for precise TNBC patient stratification for clinical studies.展开更多
Background:Triple-negative breast cancer(TNBC)has long been a difficult therapeutic target to overcome because of its extreme aggressiveness,poor efficacy and rarity of available treatment regimens.To explore the anti...Background:Triple-negative breast cancer(TNBC)has long been a difficult therapeutic target to overcome because of its extreme aggressiveness,poor efficacy and rarity of available treatment regimens.To explore the anti-TNBC potential of Caulis Polygoni Multiflori(CPM),this investigation applied an integrated computational and experimental approach.Methods:Bioactive CPM compounds were investigated via screening of three TCM databases(TCMSP,TCMID,and HERB)using Bioavailability(OB≥30%)as inclusion criteria.TNBC targets were obtained from the online resources GeneCards,CTD,and OMIM network pharmacology analysis was used to determine common target(s),utilizing two PPI analysis tools–STRING and Cytoscape.Molecular docking assessed target-compound interactions by means of AutoDock Vina.In vitro studies conducted on MDA-MB-231 cells involved evaluating inhibitory effects via MTT,wound-healing assay,transwell,and qPCR techniques.Results:Six bioactive compounds were identified,with emodin(IC_(50) approximately 15μM)and chrysophanol(IC50 approximately 25μM)showing strong binding to TNBC targets(emodin-HSP90AB1:−9.42 kcal/mol;chrysophanol-SRC:−8.32 kcal/mol).Network analysis revealed 143 shared targets,with BCL2,EGFR and ESR1 as key nodes.Pathway analysis implicated PI3K-AKT signaling and apoptosis.In vitro,emodin and chrysophanol synergistically inhibited proliferation,migration and invasion,while downregulating BCL2,EGFR and ESR1 expression.Conclusion:To the best of our knowledge,this is the first report that describes the synergistic mechanisms of multiple compounds from the extract of CPM in TNBC with chrysophanol and emodin working as the main components by mediating oncogenic pathways.展开更多
The hydrophobic sonosensitizer IR780 iodide(IR780)was loaded into liposomes to form Liposome@IR780 nanoparticles(NPs)for triple-negative breast cancer(TNBC)to enhance SDT via low-intensity ultrasound(LIU)irradiation.T...The hydrophobic sonosensitizer IR780 iodide(IR780)was loaded into liposomes to form Liposome@IR780 nanoparticles(NPs)for triple-negative breast cancer(TNBC)to enhance SDT via low-intensity ultrasound(LIU)irradiation.The NPs were characterized using various physicochemical methods including size distribution,zeta potential,and morphology.In vitro experiments show that the Liposome@IR780 NPs can generate more reactive oxygen species(ROS)upon LIU irradiation.The apoptosis experiment results further demonstrate that Liposome@IR780 NPs show better apoptosis rate against 4T1 cells.Our results indicate that Liposome@IR780 NPs will provide a promising approach for TNBC upon SDT treatment.展开更多
Triple-negative bresst canær(TNBC)metastscis is particularly severe due to its aggressive nsture,leading to rapid disease progresion and significantly reduced survival rates.Rujifang(RJF),a traditional Chinese fo...Triple-negative bresst canær(TNBC)metastscis is particularly severe due to its aggressive nsture,leading to rapid disease progresion and significantly reduced survival rates.Rujifang(RJF),a traditional Chinese formula,has demonstrated potential anti-tumor effects and theability to inhibit TNBC metastasis.However,the efects af varying R.IF dors remain undear.This study utilized Laser-based in vino fow cytometry(IVFC)to monitor circulating tumor cells(CTCs)and evaluate the efficacy of R.IF at different doses.The results indicated that R.IF at the high dose inhibited both the number af CTC:and the formaton of metatatic foci more eflectively compared to the lower dose.TUNEL assays revealed that R.IF trentment promotes apoptosis of tumor cells,with a more pronounced effect observed at the higher dose.Immuno-fluorescence experiments demonstrated that administering a higher dose of R.IF suppreses theеxprescion of Kindlin-1 more effectively in the tumor microenvironment.Although higher doses showed enhanced efficacy,they might also lesd to an increase in side efects.These findings underscore the promise and challenges of using R.IF at high doses for anti-tumor therspy.They highlight the criticnl importance of optimizing the dose of R.JP in the treatment of TNBC and provide valuable insights for its dinical application.展开更多
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 the National Natural Science Foundation of China(Nos.82102917 and 81672380)State Key Laboratory of Advanced Drug Delivery and Release Systems(No.DSQZ-QN-20250106)+2 种基金Nanjing Medical Science and Technology Development Program(Nos.YKK23104 and ZKX23012)2024-Shining Across China-Medicinal Research Fund(No.Z04J2023E095)Crosswise Project of Nanjing University(No.2020-K001).
文摘To address the issue of PD-1 inhibitor resistance driven by the immunosuppressive tumor microenvironment in triple-negative breast cancer(TNBC),we constructed activated platelet membrane-derived vesicles for targeted delivery of hemopexin(HPX)small interfering RNA(siRNA)(APP@siHPX),which effectively reduced the extracellular transport of heme and inhibited heme-mediated thrombospondin-1(TSP-1)release,leading to decreased tumor-associated macrophage(TAM)recruitment and reprogramming of TAMs from the M2 phenotype to the M1 phenotype.Consequently,combining APP@siHPX with PD-1 inhibitors synergistically alleviates T-cell immunosuppression and increases CD8^(+)T-cell activity,resulting in significant tumor growth inhibition.In summary,our results demonstrate that targeting the HPX-heme-TSP-1 axis via APP@siHPX represents a promising strategy for enhancing the efficacy of immune checkpoint inhibitors 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.
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.
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.
文摘Objectives:Triple-negative breast cancer(TNBC)presents a major treatment challenge due to its aggressive behavior.The dysfunction of the Golgi apparatus(GA)contributes to the development of various cancers.This study aimed to utilize GA-related genes(GARGs)to forecast the prognosis and immune profile of TNBC.Methods:The data were downloaded from The Cancer Genome Atlas(TCGA)database,including 175 TNBC and 99 healthy samples.The differentially expressed GARGs(DEGARGs)were analyzed using the TCGA biolinks package.The patients with TNBC were classified into two clusters utilizing the ConsensusClusterPlus package according to prognosis-related DEGARGs,followed by comparing the differences in prognosis and immune infiltration between the two clusters.Next,LASSO and stepwise Cox regression were applied to establish a GARGs signature to forecast the TNBC prognosis.The association of the GARGs signature with immune infiltrates and drug sensitivity was further explored.Results:In total,430 DEGARGs were identified between TNBC and healthy samples,among which 20 were related to TNBC prognosis.Two GARG-related molecular clusters associated with different survival times and immune heterogeneity were identified.A risk model for TNBC was established based on six GARGs,and the high-risk(HR)group exhibited a poor prognosis.The HR group demonstrated a distinctly high M2 macrophage infiltration and low M1 macrophage infiltration,which contributed to an immunosuppressive tumor microenvironment and thus led to poor prognosis of the HR group.Immune dysfunction scores and programmed cell death ligand 1(PD-L1)expression were substantially elevated in the HR group.The HR group showed increased sensitivity to anticancer drugs,such as cisplatin.Conclusion:Our findings suggest that GARGs are involved in the pathogenesis of TNBC and provide new insights into prognostic prediction.The identified clusters and GARGs signatures have the potential to guide individualized therapy.
基金supported by the Department of Biotechnology(DBT),Government of India(BT/556/NE/U-Excel/).
文摘The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer(TNBC).Recent research indicates the aberrant expression of diverse tyrosine kinases(TKs)within this cancer,contributing significantly to tumor cell proliferation,survival,invasion,and migration.The contemporary paradigm shift towards precision medicine has highlighted TKs and their receptors as promising targets for pharmacotherapy against a range of malignancies,given their pivotal roles in tumor initiation,progression,and advancement.Intensive investigations have focused on various monoclonal antibodies(mAbs)and small molecule inhibitors that specifically target proteins such as epidermal growth factor receptor(EGFR),vascular endothelial growth factor(VEGF),vascular endothelial growth factor receptor(VEGFR),cellular mesenchymal-epithelial transition factor(c-MET),human epidermal growth factor receptor 2(HER2),among others,for combating TNBC.These agents have been studied both in monotherapy and in combination with other chemotherapeutic agents.Despite these advances,a substantial terrain of unexplored potential lies within the realm of TK-targeted therapeutics,which hold promise in reshaping the therapeutic landscape.This review summarizes the various TK-targeted therapeutics that have undergone scrutiny as potential therapeutic interventions for TNBC,dissecting the outcomes and revelations stemming from diverse clinical investigations.A key conclusion from the umbrella clinical trials evidences the necessity for in-depth molecular characterization of TNBC for the maximum efficiency of TK-targeted therapeutics,either as standalone treatments or a combination.Moreover,our observation highlights that the outcomes of TK-targeted therapeutics in TNBC are substantially influenced by the diversity of the patient cohort,emphasizing the prioritization of individual patient genetic/molecular profiles for precise TNBC patient stratification for clinical studies.
基金supported by 2022 Anhui University Research Project(grant numbers No.2022AH051162)2023 Anhui University Collaborative innovation project(grant numbers No.GXXT-2023-074)National Key Clinical Collaboration Project for Difficult and Complex Diseases(Ovarian Malignancies)Integrating Traditional Chinese and Western Medicine(grant numbers National Traditional Chinese Medicine Comprehensive Development Document(2024)No.3).
文摘Background:Triple-negative breast cancer(TNBC)has long been a difficult therapeutic target to overcome because of its extreme aggressiveness,poor efficacy and rarity of available treatment regimens.To explore the anti-TNBC potential of Caulis Polygoni Multiflori(CPM),this investigation applied an integrated computational and experimental approach.Methods:Bioactive CPM compounds were investigated via screening of three TCM databases(TCMSP,TCMID,and HERB)using Bioavailability(OB≥30%)as inclusion criteria.TNBC targets were obtained from the online resources GeneCards,CTD,and OMIM network pharmacology analysis was used to determine common target(s),utilizing two PPI analysis tools–STRING and Cytoscape.Molecular docking assessed target-compound interactions by means of AutoDock Vina.In vitro studies conducted on MDA-MB-231 cells involved evaluating inhibitory effects via MTT,wound-healing assay,transwell,and qPCR techniques.Results:Six bioactive compounds were identified,with emodin(IC_(50) approximately 15μM)and chrysophanol(IC50 approximately 25μM)showing strong binding to TNBC targets(emodin-HSP90AB1:−9.42 kcal/mol;chrysophanol-SRC:−8.32 kcal/mol).Network analysis revealed 143 shared targets,with BCL2,EGFR and ESR1 as key nodes.Pathway analysis implicated PI3K-AKT signaling and apoptosis.In vitro,emodin and chrysophanol synergistically inhibited proliferation,migration and invasion,while downregulating BCL2,EGFR and ESR1 expression.Conclusion:To the best of our knowledge,this is the first report that describes the synergistic mechanisms of multiple compounds from the extract of CPM in TNBC with chrysophanol and emodin working as the main components by mediating oncogenic pathways.
文摘The hydrophobic sonosensitizer IR780 iodide(IR780)was loaded into liposomes to form Liposome@IR780 nanoparticles(NPs)for triple-negative breast cancer(TNBC)to enhance SDT via low-intensity ultrasound(LIU)irradiation.The NPs were characterized using various physicochemical methods including size distribution,zeta potential,and morphology.In vitro experiments show that the Liposome@IR780 NPs can generate more reactive oxygen species(ROS)upon LIU irradiation.The apoptosis experiment results further demonstrate that Liposome@IR780 NPs show better apoptosis rate against 4T1 cells.Our results indicate that Liposome@IR780 NPs will provide a promising approach for TNBC upon SDT treatment.
基金supported by the National Key Re-search and Development Program of China(2021YFF0502900,2019YFC1604604)the grant of Peak Climbing Project of Foshan Hospital of Tra-ditional Chinese Medicine,Traditional Chinese Medicine Bureat of Guangdong Province Project(No.20213018)+2 种基金the Special Fund for Research on National Major Research Instruuments of China(Grant No.62027824)Scientific Research Fund of Education Department of Yunnan Province(2023Y0619)Biomedical Projects of Yun-nan Key Science and Technology Program(202302AA310046).
文摘Triple-negative bresst canær(TNBC)metastscis is particularly severe due to its aggressive nsture,leading to rapid disease progresion and significantly reduced survival rates.Rujifang(RJF),a traditional Chinese formula,has demonstrated potential anti-tumor effects and theability to inhibit TNBC metastasis.However,the efects af varying R.IF dors remain undear.This study utilized Laser-based in vino fow cytometry(IVFC)to monitor circulating tumor cells(CTCs)and evaluate the efficacy of R.IF at different doses.The results indicated that R.IF at the high dose inhibited both the number af CTC:and the formaton of metatatic foci more eflectively compared to the lower dose.TUNEL assays revealed that R.IF trentment promotes apoptosis of tumor cells,with a more pronounced effect observed at the higher dose.Immuno-fluorescence experiments demonstrated that administering a higher dose of R.IF suppreses theеxprescion of Kindlin-1 more effectively in the tumor microenvironment.Although higher doses showed enhanced efficacy,they might also lesd to an increase in side efects.These findings underscore the promise and challenges of using R.IF at high doses for anti-tumor therspy.They highlight the criticnl importance of optimizing the dose of R.JP in the treatment of TNBC and provide valuable insights for its dinical application.
