Analysis of Differential Gene Expression and Core Canonical Pathways Involved in the Epithelial to Mesenchymal Transition of Triple Negative Breast Cancer Cells by Ingenuity Pathway Analysis

Triple Negative Breast Cancer (TNBC) is a malignant form of cancer with very high mortality and morbidity. Epithelial to Mesenchymal Transition (EMT) is the most common pathophysiological change observed in cancer cells of epithelial origin that promotes metastasis, drug resistance and cancer stem cell formation. Since the information regarding differential gene expression in TNBC cells and cell signaling events leading to EMT is limited, this investigation was done by comparing transcriptomic data generated by RNA isolation and sequencing of a EMT model TNBC cell line in comparison to regular TNBC cells. RNA sequencing and Ingenuity Pathway Software Analysis (IPA) of the transcriptomic data revealed several upregulated and downregulated gene expressions along with novel core canonical pathways including Sirtuin signaling, Oxidative Phosphorylation and Mitochondrial dysfunction events involved in EMT changes of the TNBC cells.

Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo

OBJECTIVE To discover a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and exploreits potential mechanisms.METHODS ULK1 expression was analyzed by The Cancer Genome Atlas(TCGA)analysis and tissue microarray(TMA)analysis.ULK1agonist was designed by using in silico screening,as well as modified by chemical synthesis and screened by kinase and anti-proliferative activities.The amino acid residues that key to the activation site of LYN-1604 were determined by site-directed mutagenesis,as well as in vitro kinase assay and ADP-Glo kinase assay.The mechanisms of LYN-1604 induced cell death were investigated by fluorescence microscope,western blotting,flow cytometry analysis,immunocytochemistry,as well as si RNA and GFP-m RFP-LC3 plasmid transfections.Potential ULK1 interactors were discovered by performing comparative microarray analysis and the therapeutic effect of LYN-1604 was assessed by xenograft breast cancer mouse model.RESULTS We found that ULK1 was remarkably downregulated in breast cancer tissue samples,especial y in triple negative breast cancer(TNBC).32 candidate smal molecules were synthesized,and we discovered a small molecule named LYN-1604 as the best candidate ULK1agonist.Additionally,we identified that three amino acid residues(LYS50,LEU53 and TYR89)were key to the activation site of LYN-1604 and ULK1.Subsequently,we demonstrated that LYN-1604 could induce autophagy-associated cell death via ULK complex(ULK1-m ATG13-FIP200-ATG101)in MDA-MB-231 cells.We also found that LYN-1604 induced cell death involved in ATF3,RAD21 and caspase 3,accompanied with autophagy and apoptosis.Moreover,we demonstrated that LYN-1604 had a good therapeutic potential on TNBC by targeting ULK1-modulated cell death in vivo.CONCLUSION We discovered a small molecule(LYN-1604)has therapeutic potential by targeting ULK1-modulated cell death associated with autophagy and apoptosis of TNBC in vitro and in vivo,which could be utilized as a new anti-TNBC drug candidate.

Triple negative breast cancer: special histological types and emerging therapeutic methods

Triple negative breast cancer(TN BC)is a complex and malignant breast cancer subtype that lacks expression of the estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor 2(H ER2),thereby making therapeutic targeting difficult.TNBC is generally considered to have high malignancy and poor prognosis.However,patients diagnosed with certain rare histomorphologic subtypes of TNBC have better prognosis than those diagnosed with typical triple negative breast cancer.In addition,with the discovery and development of novel treatment targets such as the androgen receptor(AR),PI3K/AKT/mTOR and AMPK signaling pathways,as well as emerging immunotherapies,the therapeutic options for TNBC are increasing.In this paper,we review the literature on various histological types of TNBC and focus on newly developed therapeutic strategies that target and potentially affect molecular pathways or emerging oncogenes,thus providing a basis for future tailored therapies focused on the mutational aspects of TNBC.

RNA-seq analysis identified hormone-related genes associated with prognosis of triple negative breast cancer

Triple negative breast cancer(TNBC) is an aggressive subtype of breast cancer that currently lacks effective biomarkers and therapeutic targets required to investigate the diagnosis and treatment of TNBC. Here we performed a comprehensive differential analysis of 165 TNBC samples by integrating RNA-seq data of breast tumor tissues and adjacent normal tissues from both our cohort and The Cancer Genome Atlas(TCGA). Pathway enrichment analysis was conducted to evaluate the biological function of TNBC-specific expressed genes. Further multivariate Cox proportional hazard regression was performed to evaluate the effect of these genes on TNBC prognosis. In this report, we identified a total of 148 TNBC-specific expressed genes that were primarily enriched in mammary gland morphogenesis and hormone levels related pathways, suggesting that mammary gland morphogenesis might play a unique role in TNBC patients differing from other breast cancer types. Further survival analysis revealed that nine genes(FSIP1, ADCY5, FSD1, HMSD, CMTM5, AFF3, CYP2 A7, ATP1 A2,and C11 orf86) were significantly associated with the prognosis of TNBC patients, while three of them(ADCY5,CYP2 A7, and ATP1 A2) were involved in the hormone-related pathways. These findings indicated the vital role of the hormone-related genes in TNBC tumorigenesis and may provide some independent prognostic markers as well as novel therapeutic targets for TNBC.

Overview of recent advances in metastatic triple negative breast cancer

Metastatic triple negative breast cancer(TNBC)has an aggressive phenotype with a predilection for visceral organs and brain.Best responses to chemotherapy are predominately in the first line.Recent studies have demonstrated improved progression free survival with the combination of atezolizumab/pembrolizumab and chemotherapy in programmed death-ligand 1 positive metastatic TNBC.However,a recent trial in a similar population showed no benefit for atezolizumab and paclitaxel which led to a Food and Drug Administration alert.Two phase III trials(OLYMPIAD and BROCADE3)demonstrated a benefit in progression free survival(PFS)but not overall survival in patients with BRCAassociated metastatic TNBC treated with Olaparib or Talazoparib respectively.For those treated with Talazoparib,the time to deterioration in health related-quality of life was also longer compared to chemotherapy.The BROCADE3 trial demonstrated that the combination of a platinum and veliparib increased PFS in first-line metastatic TNBC but at the cost of increased toxicity.There are no headto-head comparisons of a poly(adenosine diphosphate-ribose)polymerase inhibitors(PARPi)and platinums.There are unanswered questions regarding the role of PARPi maintenance after platinum therapy as is standard of care in BRCAassociated ovarian cancer.Other areas of therapeutic interest include targeting aberrations in the phosphoinositide 3-kinase pathway,protein kinase B,mammalian target of rapamycin or utilising antibody drug conjugates.This review focusses on recent and emerging therapeutic options in metastatic TNBC.We searched PubMed,clinicaltrials.gov and recent international meetings from American Society of Clinical Oncology,San Antonio Breast Cancer Conference and the European Society of Medical Oncology.

Inhibition of growth and metastasis of triple-negative breast cancer targeted by Traditional Chinese Medicine Tubeimu in orthotopic mice models

Objective： Triple-negative breast cancer（TNBC） is highly invasive and metastatic, which is in urgent need of transformative therapeutics. Tubeimu（TBM）, the rhizome of Bolbostemma paniculatum（Maxim.） Franquet, is one of the Chinese medicinal herbs used for breast diseases since the ancient times. The present study evaluated the efficacy, especially the anti-metastatic effects of the dichloromethane extract of Tubeimu（ETBM） on TNBC orthotopic mouse models and cell lines.Methods： We applied real-time imaging on florescent orthotopic TNBC mice model and tested cell migration and invasion abilities with MDA-MB-231 cell line. Digital gene expression sequencing was performed and Kyoto Encyclopedia of Genes and Genomes（KEGG） analysis applied to explore the pathways influenced by ETBM.Moreover, quantitative real-time polymerase chain reactions（q RT-PCR） and Western blot were delivered to confirm the gene expression changes.Results： ETBM exhibited noticeable control on tumor metastasis and growth of TNBC tumors with no obvious toxicity. In compliance with this, it also showed inhibition of cell migration and invasion in vitro. Its impact on the changed biological behavior in TNBC may be a result of decreased expression of integrin β1（ITGβ1）, integrin β8（ITGβ8） and Rho GTPase activating protein 5（ARHGAP5）, which disabled the focal adhesion pathway and caused change in cell morphology.Conclusions： This study reveals that ETBM has anti-metastatic effects on MDA-MB-231-GFP tumor and may lead to a new therapeutic agent for the integrative treatment of highly invasive TNBC.

Why natural killer cells in triple negative breast cancer?

The triple-negative subtype of breast cancer(TNBC)has the bleakest prognosis,owing to its lack of either hormone receptor as well as human epidermal growth factor receptor 2.Henceforth,immunotherapy has emerged as the front-runner for TNBC treatment,which avoids potentially damaging chemotherapeutics.However,despite its documented association with aggressive side effects and developed resistance,immune checkpoint blockade continues to dominate the TNBC immunotherapy scene.These immune checkpoint blockade drawbacks necessitate the exploration of other immunotherapeutic methods that would expand options for TNBC patients.One such method is the exploitation and recruitment of natural killer cells,which by harnessing the innate rather than adaptive immune system could potentially circumvent the downsides of immune checkpoint blockade.In this review,the authors will elucidate the advantageousness of natural killer cell-based immuno-oncology in TNBC as well as demonstrate the need to more extensively research such therapies in the future.

Forkhead box P3 and indoleamine 2,3-dioxygenase co-expression in Pakistani triple negative breast cancer patients

BACKGROUND Forkhead box P3(FOXP3)is a specific marker for immunosuppressive regulatory T(T-reg)cells.T-regs and an immunosuppressive enzyme,indoleamine 2,3-dioxygenase(IDO),are associated with advanced disease in cancer.AIM To evaluate the co-expression of FOXP3 and IDO in triple negative breast cancer(TNBC)with respect to hormone-positive breast cancer patients from Pakistan.METHODS Immunohistochemistry was performed to analyze the expression of FOXP3,IDO,estrogen receptor,progesterone receptor,and human epidermal growth factor receptor on tissues of breast cancer patients(n=100):Hormone-positive breast cancer(n=51)and TNBC(n=49).A total of 100 patients were characterized as FOXP3 negative vs positive and further categorized based on low,medium,and high IDO expression score.Univariate and multivariate logistic regression models were used.RESULTS Out of 100 breast tumors,25%expressed FOXP3 positive T-regs.A significant coexpression of FOXP3 and IDO was observed among patients with TNBC(P=0.01)compared to those with hormone-positive breast cancer.Two variables were identified as significant independent risk factors for FOXP3 positive:IDO expression high(adjusted odds ratio(AOR)5.90;95%confidence interval(CI):1.22-28.64;P=0.03)and TNBC(AOR 2.80;95%CI:0.96-7.95;P=0.05).CONCLUSION Our data showed that FOXP3 positive cells might be associated with high expression of IDO in TNBC patients.FOXP3 and IDO co-expression may also suggest its involvement in disease,and evaluation of FOXP3 and IDO expression in TNBC patients may offer a new therapeutic option.

Effects of TAM-derived exosomes on migration and invasion of MDA-MB- 231 cells in triple negative breast cancer

Objective:To investigate the effects of exosomes derived from tumor-associated macrophages(TAMs)on migration and invasion of MDA-MB-231 cells in triple negative breast cancer.Methods:The MDA-MB-231 cells,a human breast cancer cell line,were divided into the experimental group and the blank control group.The exosomes were isolated from the supernatant of human peripheral blood mononuclear cells(THP-1)by a multi-step ultracentrifugal procedure.The effects of exosomes on migration and invasion of MDAMB-231 cells were studied by endocytosis assay of exosomes,Transwell migration assay and Celigo scratch assay.Results:Exosomes were ingested and endocytosed by MDAMB-231 cells,brought into the cytoplasm at 3h and enriched significantly at 6h.Compared with the blank control group,the number of metastatic cells in the Transwell compartment(241±3.35)and its variation relative to normal cells(144±2.33)in the experimental group were significantly increased(P<0.05).The 24 h migration rate of MDA-MB-231 cells treated with exosomes in the scratch assay showed similar results(39.86±3.47 in the experimental group vs.24.48±2.97 in the control group,P<0.05).Conclusion:TAM-derived exosomes can be ingested and endocytosed by MDA-MB-231 cells,and promote their migration and invasion in vitro.

P53 gene could be a new effective therapeutic target in triple-negative breast cancer: a Meta-analysis

Objective： The aim of this study was to explore the relationship between p53 gene and triple-negative breast cancer （TNBC）, and determine that whether p53 gene could be a new effective therapeutic target. Methods： We identified studies with quantitative data on the relation of p53 gene and TNBC through searching 12 databases online （Oct. 1999-Oct. 2012） and reviewing the references, which were written in English or Chinese. Summary estimates of odds ratio （OR） was calculated using the fixed-effects model or the random-effects model as appropriate. Results： We identified 12 eligible stud- ies with 1532 cases of TNBC patients and 6329 controls of non-TNBC patients. The test for homogeneity resulted in X^2 = 200.16 （P 〈 0.05）, it showed significant heterogeneity so that a random effect model was applied. Our results showed that the expression of p53 gene could be much stronger in TNBC group than that in non-TNBC group [OR = 2.10, 95% confidence interval （CI） = 1.21-3.65]. In ethnicity-subgroup analysis, we found that in Caucasian group, the expression of p53 gene were stronger in TNBC group （OR = 2.60, 95% CI = 1.21-5.57）, but there was no statistical significance in Asian group （OR = 1.69, 95% CI = 0.83-3.45）. Conclusion： P53 gene could be an effective predictor and a good therapeutic target for TNBC patients in the future, especially in Caucasian. Further researches focusing on p53 gene would gain a breakthrough in the treatment of TNBC.

Pattern of Recurrence in Radically Treated Triple Negative Breast Cancer Patients

Background: In India approximately 20% of the patients with breast cancer are triple receptor negative. Owing to the aggressive nature and shorter disease-free survival judicious follow up and identification of failure pattern will benefit the patient. Similar studies have been conducted among non-Hispanic population and in China. This study aims to identify failure pattern in radically treated breast cancer patients who are triple receptor negative among Indian population. Methods: This prospective observational study was conducted in the Department of Radiation Oncology, a tertiary cancer centre in Kerala, India. The objective was to record the pattern of recurrence among triple negative breast cancer patients who completed their planned radical treatment. 171 patients with triple negative breast cancer were included in the study. Patients who completed the planned radical treatment were kept under regular follow up. Details of clinical examination and investigations during the follow up were recorded periodically. Results: Out of 171 patients 30 patients had a recurrence of disease. Median age of the population was 53 years. Among the 30 patients who had a recurrence, 16 patients (53%) had systemic relapse and 14 patients (47%) had locoregional relapse. Lung was found to be the most common site of distant metastasis (37%). Ipsilateral chest wall was found to be the most common site of locoregional relapse (50%). 6 months disease free survival was found to be 91.8% and 1-year disease free survival was found to be 70.2%. Conclusion: Among radically treated triple negative breast cancers relapses, systemic recurrence was more than locoregional recurrences.

Early Stage Triple Negative Breast Cancer Has Significantly Better Outcomes than More Advanced Disease: A Single Centre Retrospective Review

A retrospective, serial analysis of 181 triple negative breast cancer (TNBC) patients was undertaken at a regional cancer centre in Canada. The primary focus of the analysis was to investigate the effect of presenting stage in patients with TNBC on progression free and overall survival. We were able to demonstrate that patients presenting with an earlier stage breast cancer had a significantly superior progression free and overall survival when compared to more advanced stage. The adjusted multivariate cox-regression analyses for the overall and progression free survival suggest that the hazard of death was significantly lower for patients with stages I (HR = 0.09;95% CI 0.03 - 0.24) and II (HR = 0.29;95% CI 0.16 - 0.54) than for patients with stage III. The only other predictor of progression free survival besides stage, was receipt of radiotherapy (HR = 0.39;95% CI 0.22 - 0.69) in the adjusted cox regression analysis. Less than 2% of patients presented with stage IV disease. The small numbers presenting with stage IV disease may have impact on the development of clinical and translational trials. Certainly there may be stage migration if staging included more standardized or more sensitive investigations such as PET scans, and this might an important consideration in developing clinical trials. Twenty-five percent of patients presented with stage I disease. It is important for patients with TNBC presenting with earlier stages of disease that they are aware that they will have a better prognosis than their counterparts with more advanced disease. It is important that we are aware of this patient population, as their treatment recommendations are unclear and a source of a fair amount of controversy currently.

Expression of MxA Protein in Triple Negative Breast Cancer and its Relationship with Prognosis

Objective:To explore the expression of human myxovirus resistance protein A(MxA)in triple negative breast cancer(TNBC)and its relationship with prognosis.Methods:144 cases of TNBC confirmed by pathology before or after surgery from January 2014 to January 2017 in the First Central Hospital of Baoding City were retrospectively collected.Western blotting was used to detect the expression of MxA protein in TNBC and adjacent breast tissues.According to the expression of MxA protein,144 TNBC patients were divided into low MxA protein expression group(n=91)and MxA protein high expression group(n=53)for subsequent comparison of prognosis of patients in between these two groups.Results:The expression of MxA protein in TNBC tissue was lower than that of adjacent breast tissue,and the difference was statistically significant(P<0.05).The patients in high MxA expression group had higher loco-regional recurrence-free rate,disease-free survival(DFS)rate,and overall survival(OS)rate than those in low MxA expression group for 3 years.On the other hand,the distant metastasis rate was lower in the high expression group compared to that in the low MxA expression group,and the difference was statistically significant(P<0.05).Conclusion:In triple-negative breast cancer,high MxA expression is a potential predictor of TNBC prognosis.

The Expression and Clinical Significance of Sema4A in Triple Negative Breast Cancer

Objective:To explore the expression and clinical significance of Sema4A in triple-negative breast cancer.Metlods:Eighty patients with invasive ductal carcinoma of the breast and 40 normal tissues adjacent to cancer were selected.Immumohistochemical methods were used to detect the expression of Sema4A in breast cancer and normal tissues adjacent to cancer,and its relationship with breast cancer clinicopathological features and prognosis.Results:The expression of Sema4a in the serum of BCA patients was significantly higher than that of healthy controls.In addition,the expression of sema4a in BCA cells and in the cell supernatants was also up-regulated under hypoxia.Conclusion:Exogenous Sema4A can protect BCA cells from hypoxia-induced cytotoxicity,inhibit cell apoptosis and promote cell proliferation.

Expression and significance of Shh,Gli1 and β-catenin in triple-negative breast cancer tissues

Objective:To detect the expression of Shh,Gli1 and β-catenin in triple negative breast cancer tissues and paracancer breast tissues by qRT-PCR and immunohistochemistry and to analyze their correlation with clinicopathological features.Methods:(1)qRT-PCR was used to detect the mRNA expression of Shh,Gli1 and β-catenin in 30 cases of triple negative breast cancer and their paracancer breast tissues,and the correlation among them was analyzed.(2)The expression of Shh,Gli1 and β-catenin proteins in 30 triple negative breast cancer and their paracancer breast tissues was detected by immunohistochemistry,and their correlation with clinicopathological features was analyzed.Results:(1)Shh mRNA expression(1.2334±0.27867),Gli1 mRNA expression(1.2135±0.20636)and β-catenin mRNA expression(1.1421±0.32330)in triple negative breast cancer tissues were higher than that in paracancer breast tissues,i.e.,Shh mRNA expression(1.0022±0.06721),Gli1 mRNA expression(1.0003±0.02420)and β-catenin mRNA expression(1.0033±0.07920)were significantly different(p<.05).There was a significantly positive correlation between the mRNA expression of Shh and Gli1(r=.989,p<.001),and between the mRNA expression of Shh and β-catenin(r=.868,p<.001).There was a significantly positive correlation between the mRNA expression of Gli1 and β-catenin expression(r=.869,p<.001).(2)The positive expression rates of Shh,Gli1 and β-catenin in triple negative breast cancer tissues were 93.3%(28/30),96.7%(29/30)and 93.3%(28/30),respectively,which were higher than those in paracancer tissues 60%(18/30),73.3%(22/30)and 73.3%(22/30),the differences were statistically significant(p<0.05).There was a significantly positive correlation between the mRNA expression of Shh and Gli1(r=.958,p<.001),and between the mRNA expression of Shh and β-catenin(r=.952,p<.001).There was a significantly positive correlation between the mRNA expression of Gli1 and β-catenin expression(r=.927,p<.001).The expression of Shh,Gli1 and β-catenin protein in triple negative breast cancer was not correlated with age and tumor size(p>.05),but Shh was positively correlated with histological grade(G)(r=.774,p<.001).Furthermore,Gli1 was positively correlated with histological grade(r=.757,p<.001).β-catenin was positively correlated with histological grade(r=.739,p<.001).Shh was positively correlated with TNM staging(r=.460,p=.010).Gli1 was positively correlated with TNM staging(r=.414,p=.023).β-catenin was positively correlated with TNM staging(r=.404,p=.027).Shh was positively correlated with lymph node metastasis(r=.540,p=.002).Gli1 was positively correlated with lymph node metastasis(r=.515,p=.004).β-catenin was positively correlated with lymph node metastasis(r=.559,p=.001).Conclusions:(1)The up-regulated expression of Shh,Gli1 and β-catenin proteins in triple negative breast cancer suggests that Shh,Gli1 and β-catenin proteins are involved in tumor genesis.The combined detection of the three proteins may provide a theoretical basis for the diagnosis and prognosis evaluation of triple negative breast cancer.(2)Shh was positively correlated with Gli1 protein expression and β-catenin protein expression.Gli1 was positively correlated with β-catenin protein expression,suggesting that the three types of proteins play a synergistic role in the occurrence and development of TNBC.There may be crosstalk in the Wnt/β-catenin and Hedgehog signaling pathways in TNBC,which may provide a new approach for the treatment of TNBC.(3)The expression of Shh,Gli1 and β-catenin proteins was correlated with the degree of differentiation,TNM staging and lymph node metastasis of triple negative breast cancer,but not correlated with age and tumor size.Therefore,it was predicted that the three types of proteins were related to the invasion,metastasis and prognosis of TNBC.

Multiomics and single‐cell sequencings reveal the specific biological characteristics of low Ki‐67 triple‐negative breast cancer

Background:Triple‐negative breast cancer(TNBC)displays high heterogeneity.The majority of TNBC cases are characterized by high Ki‐67 expression.TNBC with low Ki‐67 expression accounts for only a small fraction of cases and has been relatively less studied.Methods:This study analyzed a large single‐center multiomics TNBC data set,combined with a single‐cell data set.The clinical,genomic,and metabolic characteristics of patients with low Ki‐67 TNBC were analyzed.Results:The clinical and pathological characteristics were analyzed in 2217 TNBC patients.Low Ki‐67 TNBC was associated with a higher patient age at diagnosis,a lower proportion of invasive ductal carcinoma,increased alterations in the PI3K‐AKT‐mTOR pathway,upregulated lipid metabolism pathways,and enhanced infiltration of M2 macrophages.High Ki‐67 TNBC exhibited a higher prevalence of TP53 gene mutations,elevated nucleotide metabolism,and increased infiltration of M1 macrophages.Conclusions:We identified specific genomic and metabolic characteristics unique to low Ki‐67 TNBC,which have implications for the development of precision therapies and patient stratification strategies.

Immunostimulant nanomodulator boosts antitumor immune response in triple negative breast cancer by synergism of vessel normalization and photothermal therapy

Tumor vascular dysfunction and immune suppression predict poor outcomes of tumor therapy.Combination of photothermal therapy(PTT)and vessel normalization with tumor immunotherapy is promising to augment antitumor benefit.Herein,we develop a potential immunostimulatory nanomodulator for treatment of triple-negative breast cancer(TNBC)treatment via synergism of PTT,vessel normalization,and priming of tumoral suppressive immune microenvironment by blocking transforming growth factor-β(TGF-β)pathway.The nanomodulator,namely Vac@Apt@BPs,is developed by conjugation of TGF-βinhibitor Vactosertib(Vac)and nucleolin-recognizing aptamer(Apt)on the surface of black phosphorus nanoparticles(BPs).Vac@Apt@BPs show good accumulation in TNBC via aptamer-induced active targeting of TNBC.Via the blockade of TGF-βsignaling,Vac@Apt@BPs effectively inhibit the formation of tumor neovascular,and normalize the vessels to recover vascular integrity and alleviate the hypoxia stress.Together with the tumor eradication and immunogenic cell death via PTT,robust immune response was boosted by promoted maturation of dendritic cells,suppression of regulatory T cells,and stimulation of effective T cells.This synergistic therapeutic strategy potentially suppresses the growth of TNBC in mice.

Macrophage-camouflaged epigenetic nanoinducers enhance chemoimmunotherapy in triple negative breast cancer

Chemoimmunotherapy has been approved as standard treatment for triple-negative breast cancer(TNBC),but the clinical outcomes remain unsatisfied.Abnormal epigenetic regulation is associated with acquired drug resistance and T cell exhaustion,which is a critical factor for the poor response to chemoimmunotherapy in TNBC.Herein,macrophage-camouflaged nanoinducers co-loaded with paclitaxel(PTX)and decitabine(DAC)(P/D-mMSNs)were prepared in combination with PD-1 blockade therapy,hoping to improve the efficacy of chemoimmunotherapy through the demethylation of tumor tissue.Camouflage of macrophage vesicle confers P/D-mMSNs with tumor-homing properties.First,DAC can achieve demethylation of tumor tissue and enhance the sensitivity of tumor cells to PTX.Subsequently,PTX induces immunogenic death of tumor cells,promotes phagocytosis of dead cells by dendritic cells,and recruits cytotoxic T cells to infiltrate tumors.Finally,DAC reverses T cell depletion and facilitates immune checkpoint blockade therapy.P/D-mMSNs may be a promising candidate for future drug delivery design and cancer combination therapy in TNBC.

Tellurium-driven maple leaf-shaped manganese nanotherapeutics reshape tumor microenvironment via chemical transition in situ to achieve highly efficient radioimmunotherapy of triple negative breast cancer

The therapeutic efficacy of radioimmunotherapy against triple negative breast cancer(TNBC)is largely limited by the complicated tumor microenvironment(TME)and its immunosuppressive state.Thus developing a strategy to reshape TME is expected to achieve highly efficient radioimmunotherapy.Therefore,we designed and synthesized a tellurium(Te)-driven maple leaf manganese carbonate nanotherapeutics(MnCO3@Te)by gas diffusion method,but also provided a chemical catalytic strategy in situ to augment ROS level and activate immune cells for improving cancer radioimmunotherapy.As expected,with the help of H2O2 in TEM,MnCO3@Te heterostructure with reversible Mn3+/Mn2+transition could catalyze the intracellular ROS overproduction to amplify radiotherapy.In addition,by virtue of the ability to scavenge H+in TME by carbonate group,MnCO3@Te directly promote the maturation of dendritic cells and macrophage M1 repolarization by stimulator of interferon genes(STING)pathway activation,resulting in remodeling immuno-microenvironment.As a result,MnCO3@Te synergized with radiotherapy and immune checkpoint blockade therapy effectively inhibited the breast cancer growth and lung metastasis in vivo.Collectively,these findings indicate that MnCO3@Te as an agonist,successfully overcome radioresistance and awaken immune systems,showing promising potential for solid tumor radioimmunotherapy.

Paclitaxel-induced stress granules increase LINE-1 mRNA stability to promote drug resistance in breast cancer cells

Abnormal expression of long interspersed element-1(LINE-1)has been implicated in drug resistance,while our previous study showed that chemotherapy drug paclitaxel(PTX)increased LINE-1 level with unknown mechanism.Bioinformatics analysis suggested the regulation of LINE-1 mRNA by drug-induced stress granules(SGs).This study aimed to explore whether and how SGs are involved in drug-induced LINE-1 increase and thereby promotes drug resistance of triple negative breast cancer(TNBC)cells.We demonstrated that SGs increased LINE-1 expression by recruiting and stabilizing LINE-1 mRNA under drug stress,thereby adapting TNBC cells to chemotherapy drugs.Moreover,LINE-1 inhibitor efavirenz(EFV)could inhibit drug-induced SG to destabilize LINE-1.Our study provides the first evidence of the regulation of LINE-1 by SGs that could be an important survival mechanism for cancer cells exposed to chemotherapy drugs.The findings provide a useful clue for developing new chemotherapeutic strategies against TNBCs.