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: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
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
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
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
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
Objectives:Deubiquitinase OTUB2 plays a critical role in the progression of various tumors.However,its specific role in triple-negative breast cancer(TNBC)remains unclear.This study aims to elucidate the biological fu...Objectives:Deubiquitinase OTUB2 plays a critical role in the progression of various tumors.However,its specific role in triple-negative breast cancer(TNBC)remains unclear.This study aims to elucidate the biological function of OTUB2 in TNBC and uncover the underlying mechanisms.Methods:First,we found that the expression of OTUB2 was upregulated in TNBC by bioinformatics analysis,we then validated its expression in TNBC tissues and cells using immunohistochemistry(IHC)and qPCR and plotted the survival curves by Kaplan-Meier method.Gene set enrichment analysis(GSEA)suggested that OTUB2 may be involved in tumor proliferation and metastasis.Further functional assays,including Cell Counting Kit-8(CCK-8),colony formation,Transwell,and wound healing assays,were performed to assess the effects of OTUB2 overexpression and knockdown on TNBC cell proliferation and migration.Additionally,UbiBrowser 2.0 was used to identify OTUB2 substrate proteins and western blotting was conducted to clarify the molecular mechanisms involved.Results:Our results demonstrated that OTUB2 expression was elevated in TNBC and associated with poor prognosis.Overexpression of OTUB2 enhanced the proliferation and migration of TNBC cells,while its knockdown inhibited these processes.Moreover,OTUB2 stabilized tumor necrosis factor receptor-associated factor 6(TRAF6)by deubiquitinating it,leading to activation of the protein kinase B(AKT)pathway.Conclusions:OTUB2 exerts its promoting effects on the progression of TNBC by activating the TRAF6/AKT pathway.展开更多
Triple-negative breast cancer(TNBC)is a highly heterogeneous and aggressive subtype of breast cancer characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor re...Triple-negative breast cancer(TNBC)is a highly heterogeneous and aggressive subtype of breast cancer characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor receptor 2(HER2)expression.Due to the lack of specific molecular targets,TNBC does not respond to conventional hormone or HER2-targeted therapies,posing a major challenge in breast cancer treatment.In recent years,molecular biomarkers have shown significant promise in the diagnosis,prognosis,and personalized treatment of TNBC.In-depth investigation of these biomarkers may lead to the development of more effective diagnostic and therapeutic strategies,ultimately improving patient outcomes.This review focuses on recent research progress concerning key molecular biomarkers in TNBC and explores their potential clinical applications,aiming to provide a theoretical basis for the advancement of precision therapy in TNBC.展开更多
Chemotherapy has been recommended as the standard protocol for triple-negative breast cancer(TNBC)at the advanced stage.However,the current treatment is unsatisfactory due to inefficient drug accumulation and rapid ch...Chemotherapy has been recommended as the standard protocol for triple-negative breast cancer(TNBC)at the advanced stage.However,the current treatment is unsatisfactory due to inefficient drug accumulation and rapid chemo-resistance.Thus,rational design of advanced drug delivery systems that can induce multiple cell death pathways is a promising strategy to combat TNBC.Ferroptosis is a powerful non-apoptotic cell death modality,showing potential in tumor inhibition.Herein,we propose a binary prodrug nanoassemblies that combines chemotherapy with ferroptosis for TNBC treatment.In this system,paclitaxel is linked with paracetamol(ferroptosis activator)by a disulfide linkage to construct self-assembly prodrug.Meanwhile,2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-methyl(polyethylene glycol)-2000-tyrosine(DSPE-PEG2k-tyrosine)is applied for large neutral amino acid transporter 1(LAT1)targeting,which is highly expressed in TNBC.The prodrug nanoassemblies exhibit good stability and a glutathione(GSH)-responsive release profile.Furthermore,the LAT1-targeted nanoassemblies show stronger cytotoxicity,higher cellular uptake,and more obvious ferroptosis activation than non-decorated ones.In a TNBC mice model,the prodrug nanoassemblies demonstrate strong anti-tumor efficacy.The application of ferroptosis-assisting chemotherapy may provide a promising strategy for TNBC therapy.展开更多
Dose-dense chemotherapy is the preferred first-line therapy for triple-negative breast cancer(TNBC),a highly aggressive disease with a poor prognosis.This treatment uses the same drug doses as conventional chemotherap...Dose-dense chemotherapy is the preferred first-line therapy for triple-negative breast cancer(TNBC),a highly aggressive disease with a poor prognosis.This treatment uses the same drug doses as conventional chemotherapy but with shorter dosing intervals,allowing for promising clinical outcomes with intensive treatment.However,the frequent systemic administration used for this treatment results in systemic toxicity and low patient compliance,limiting therapeutic efficacy and clinical benefit.Here,we report local dose-dense chemotherapy to treat TNBC by implanting 3D printed devices with timeprogrammed pulsatile release profiles.The implantable device can control the time between drug releases based on its internal microstructure design,which can be used to control dose density.The device is made of biodegradable materials for clinical convenience and designed for minimally invasive implantation via a trocar.Dose density variation of local chemotherapy using programmable release enhances anti-cancer effects in vitro and in vivo.Under the same dose density conditions,device-based chemotherapy shows a higher anticancer effect and less toxic response than intratumoral injection.We demonstrate local chemotherapy utilizing the implantable device that simulates the drug dose,number of releases,and treatment duration of the dose-dense AC(doxorubicin and cyclophosphamide)regimen preferred for TNBC treatment.Dose density modulation inhibits tumor growth,metastasis,and the expression of drug resistance-related proteins,including p-glycoprotein and breast cancer resistance protein.To the best of our knowledge,local dose-dense chemotherapy has not been reported,and our strategy can be expected to be utilized as a novel alternative to conventional therapies and improve anti-cancer efficiency.展开更多
Breast cancer remains a leading cause of mortality in women worldwide.Triple-negative breast cancer(TNBC)is a particularly aggressive subtype characterized by rapid progression,poor prognosis,and lack of clear therape...Breast cancer remains a leading cause of mortality in women worldwide.Triple-negative breast cancer(TNBC)is a particularly aggressive subtype characterized by rapid progression,poor prognosis,and lack of clear therapeutic targets.In the clinic,delineation of tumor heterogeneity and development of effective drugs continue to pose considerable challenges.Within the scope of our study,high heterogeneity inherent to breast cancer was uncovered based on the landscape constructed from both tumor and healthy breast tissue samples.Notably,TNBC exhibited significant specificity regarding cell proliferation,differentiation,and disease progression.Significant associations between tumor grade,prognosis,and TNBC oncogenes were established via pseudotime trajectory analysis.Consequently,we further performed comprehensive characterization of the TNBC microenvironment.A crucial epithelial subcluster,E8,was identified as highly malignant and strongly associated with tumor cell proliferation in TNBC.Additionally,epithelial-mesenchymal transition(EMT)-associated fibroblast and M2 macrophage subclusters exerted an influence on E8 through cellular interactions,contributing to tumor growth.Characteristic genes in these three cluster cells could therefore serve as potential therapeutic targets for TNBC.The collective findings provided valuable insights that assisted in the screening of a series of therapeutic drugs,such as pelitinib.We further confirmed the anti-cancer effect of pelitinib in an orthotopic 4T1 tumor-bearing mouse model.Overall,our study sheds light on the unique characteristics of TNBC at single-cell resolution and the crucial cell types associated with tumor cell proliferation that may serve as potent tools in the development of effective anti-cancer drugs.展开更多
Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Method...Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Methods:We assembled a large-scale,real-world cohort comprised of 880 TNBC patients[465 early-stage TNBC(eTNBC)and 415 metastatic TNBC(mTNBC)patients]who were treated at Fudan University Shanghai Cancer Center.The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort.Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes.Results:The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1%(47/465).The median overall survival(OS)in the mTNBC cohort was 27.2 months[95%confidence interval(CI),24.4–30.2 months],which indicated a poor prognosis.The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed.Consistent molecular subtypes were maintained in 77.5%of the patients throughout disease progression with the mesenchymal-like(MES)subtype demonstrating a tendency for subtype transition and brain metastasis.Additionally,a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial.Conclusions:Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression.However,we emphasize the major importance of repeat pathologic confirmation of the MES subtype.展开更多
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 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.
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.
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supported by the National Natural Science Foundation of China(No.82373380,Xinhua Xie).
文摘Objectives:Deubiquitinase OTUB2 plays a critical role in the progression of various tumors.However,its specific role in triple-negative breast cancer(TNBC)remains unclear.This study aims to elucidate the biological function of OTUB2 in TNBC and uncover the underlying mechanisms.Methods:First,we found that the expression of OTUB2 was upregulated in TNBC by bioinformatics analysis,we then validated its expression in TNBC tissues and cells using immunohistochemistry(IHC)and qPCR and plotted the survival curves by Kaplan-Meier method.Gene set enrichment analysis(GSEA)suggested that OTUB2 may be involved in tumor proliferation and metastasis.Further functional assays,including Cell Counting Kit-8(CCK-8),colony formation,Transwell,and wound healing assays,were performed to assess the effects of OTUB2 overexpression and knockdown on TNBC cell proliferation and migration.Additionally,UbiBrowser 2.0 was used to identify OTUB2 substrate proteins and western blotting was conducted to clarify the molecular mechanisms involved.Results:Our results demonstrated that OTUB2 expression was elevated in TNBC and associated with poor prognosis.Overexpression of OTUB2 enhanced the proliferation and migration of TNBC cells,while its knockdown inhibited these processes.Moreover,OTUB2 stabilized tumor necrosis factor receptor-associated factor 6(TRAF6)by deubiquitinating it,leading to activation of the protein kinase B(AKT)pathway.Conclusions:OTUB2 exerts its promoting effects on the progression of TNBC by activating the TRAF6/AKT pathway.
基金supported by the Science and Technology Research Project of Henan Province(Grant No.252102311028)titled“Study on ECT2 as a Potential Molecular Marker and Therapeutic Target in the Diagnosis and Treatment of Breast Cancer.”。
文摘Triple-negative breast cancer(TNBC)is a highly heterogeneous and aggressive subtype of breast cancer characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor receptor 2(HER2)expression.Due to the lack of specific molecular targets,TNBC does not respond to conventional hormone or HER2-targeted therapies,posing a major challenge in breast cancer treatment.In recent years,molecular biomarkers have shown significant promise in the diagnosis,prognosis,and personalized treatment of TNBC.In-depth investigation of these biomarkers may lead to the development of more effective diagnostic and therapeutic strategies,ultimately improving patient outcomes.This review focuses on recent research progress concerning key molecular biomarkers in TNBC and explores their potential clinical applications,aiming to provide a theoretical basis for the advancement of precision therapy in TNBC.
基金supported by the National Nature Science Foundation of China(No.81803029)the Science and Technology Foundation of Yuzhong District,Chongqing(No.20210179)the Nature Science Foundation of Chongqing(No.cstc2021jcyjmsxmX1089)。
文摘Chemotherapy has been recommended as the standard protocol for triple-negative breast cancer(TNBC)at the advanced stage.However,the current treatment is unsatisfactory due to inefficient drug accumulation and rapid chemo-resistance.Thus,rational design of advanced drug delivery systems that can induce multiple cell death pathways is a promising strategy to combat TNBC.Ferroptosis is a powerful non-apoptotic cell death modality,showing potential in tumor inhibition.Herein,we propose a binary prodrug nanoassemblies that combines chemotherapy with ferroptosis for TNBC treatment.In this system,paclitaxel is linked with paracetamol(ferroptosis activator)by a disulfide linkage to construct self-assembly prodrug.Meanwhile,2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-methyl(polyethylene glycol)-2000-tyrosine(DSPE-PEG2k-tyrosine)is applied for large neutral amino acid transporter 1(LAT1)targeting,which is highly expressed in TNBC.The prodrug nanoassemblies exhibit good stability and a glutathione(GSH)-responsive release profile.Furthermore,the LAT1-targeted nanoassemblies show stronger cytotoxicity,higher cellular uptake,and more obvious ferroptosis activation than non-decorated ones.In a TNBC mice model,the prodrug nanoassemblies demonstrate strong anti-tumor efficacy.The application of ferroptosis-assisting chemotherapy may provide a promising strategy for TNBC therapy.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Ministry of Science and ICT(MSIT)(No.2021R1A2C2012808)Technology Innovation Program(Alchemist Project)(No.20012378)funded by the Ministry of Trade,Industry&Energy(MOTIE),South Korea.
文摘Dose-dense chemotherapy is the preferred first-line therapy for triple-negative breast cancer(TNBC),a highly aggressive disease with a poor prognosis.This treatment uses the same drug doses as conventional chemotherapy but with shorter dosing intervals,allowing for promising clinical outcomes with intensive treatment.However,the frequent systemic administration used for this treatment results in systemic toxicity and low patient compliance,limiting therapeutic efficacy and clinical benefit.Here,we report local dose-dense chemotherapy to treat TNBC by implanting 3D printed devices with timeprogrammed pulsatile release profiles.The implantable device can control the time between drug releases based on its internal microstructure design,which can be used to control dose density.The device is made of biodegradable materials for clinical convenience and designed for minimally invasive implantation via a trocar.Dose density variation of local chemotherapy using programmable release enhances anti-cancer effects in vitro and in vivo.Under the same dose density conditions,device-based chemotherapy shows a higher anticancer effect and less toxic response than intratumoral injection.We demonstrate local chemotherapy utilizing the implantable device that simulates the drug dose,number of releases,and treatment duration of the dose-dense AC(doxorubicin and cyclophosphamide)regimen preferred for TNBC treatment.Dose density modulation inhibits tumor growth,metastasis,and the expression of drug resistance-related proteins,including p-glycoprotein and breast cancer resistance protein.To the best of our knowledge,local dose-dense chemotherapy has not been reported,and our strategy can be expected to be utilized as a novel alternative to conventional therapies and improve anti-cancer efficiency.
基金funded by the National Natural Science Foundation of China(Grant Nos:62172131 and 81872135)the Outstanding Youth Foundation of Heilongjiang Province of China(Grant No.:YQ2021C026).
文摘Breast cancer remains a leading cause of mortality in women worldwide.Triple-negative breast cancer(TNBC)is a particularly aggressive subtype characterized by rapid progression,poor prognosis,and lack of clear therapeutic targets.In the clinic,delineation of tumor heterogeneity and development of effective drugs continue to pose considerable challenges.Within the scope of our study,high heterogeneity inherent to breast cancer was uncovered based on the landscape constructed from both tumor and healthy breast tissue samples.Notably,TNBC exhibited significant specificity regarding cell proliferation,differentiation,and disease progression.Significant associations between tumor grade,prognosis,and TNBC oncogenes were established via pseudotime trajectory analysis.Consequently,we further performed comprehensive characterization of the TNBC microenvironment.A crucial epithelial subcluster,E8,was identified as highly malignant and strongly associated with tumor cell proliferation in TNBC.Additionally,epithelial-mesenchymal transition(EMT)-associated fibroblast and M2 macrophage subclusters exerted an influence on E8 through cellular interactions,contributing to tumor growth.Characteristic genes in these three cluster cells could therefore serve as potential therapeutic targets for TNBC.The collective findings provided valuable insights that assisted in the screening of a series of therapeutic drugs,such as pelitinib.We further confirmed the anti-cancer effect of pelitinib in an orthotopic 4T1 tumor-bearing mouse model.Overall,our study sheds light on the unique characteristics of TNBC at single-cell resolution and the crucial cell types associated with tumor cell proliferation that may serve as potent tools in the development of effective anti-cancer drugs.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant No.82103039)the Program of Shanghai Academic/Technology Research Leader(Grant No.20XD1421100)the Wu Jieping Medical Foundation(Grant No.320.6750.2021-10-64).
文摘Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Methods:We assembled a large-scale,real-world cohort comprised of 880 TNBC patients[465 early-stage TNBC(eTNBC)and 415 metastatic TNBC(mTNBC)patients]who were treated at Fudan University Shanghai Cancer Center.The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort.Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes.Results:The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1%(47/465).The median overall survival(OS)in the mTNBC cohort was 27.2 months[95%confidence interval(CI),24.4–30.2 months],which indicated a poor prognosis.The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed.Consistent molecular subtypes were maintained in 77.5%of the patients throughout disease progression with the mesenchymal-like(MES)subtype demonstrating a tendency for subtype transition and brain metastasis.Additionally,a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial.Conclusions:Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression.However,we emphasize the major importance of repeat pathologic confirmation of the MES subtype.
