Super enhancer inhibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma

Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically,THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients.

N-myc downstream regulated gene 1 inhibition of tumor progression in Caco2 cells

BACKGROUND Invasion and migration are the irreversible stages of colorectal cancer(CRC).The key is to find a sensitive,reliable molecular marker that can predict the migration of CRC at an early stage.N-myc downstream regulated gene 1(NDRG1)is a multifunctional gene that has been tentatively reported to have a strong relationship with tumor invasion and migration,however the current molecular role of NDRG1 in CRC remains unknown.AIM To explore the role of NDRG1 in the development of CRC.METHODS NDRG1 stably over-expressed Caco2 cell line was established by lentiviral infection and NDRG1 knock-out Caco2 cell line was established by CRISPR/Cas9.Furthermore,the mRNA and protein levels of NDRG1 in Caco2 cells after NDRG1 over-expression and knockout were detected by real-time polymerase chain reaction and western blot.The cell proliferation rate was measured by the cell counting kit-8 method;cell cycle and apoptosis were detected by flow cytometry;invasion and migration ability were detected by the 24-transwell method.RESULTS NDRG1 over-expression inhibited Caco2 proliferation and the cell cycle could be arrested at the G1/S phase when NDRG1 was over-expressed,while the number of cells in the G2 phase was significantly increased when NDRG1 was knocked out.This suggests that NDRG1 inhibited the proliferation of Caco2 cells by arresting the cell cycle in the G1/S phase.Our data also demonstrated that NDRG1 promotes early cell apoptosis.Invasion and migration of cells were extensively inhibited when NDRG1 was over-expressed.CONCLUSION NDRG1 inhibits tumor progression in Caco2 cells which may represent a potential novel therapeutic strategy for the treatment of CRC.

Ferroptosis:a critical mechanism of N^(6)-methyladenosine modification involved in carcinogenesis and tumor progression

Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation.It occurs when multiple redoxactive enzymes are ectopically expressed or show abnormal function.Hence,the precise regulation of ferroptosis-related molecules is mediated across multiple levels,including transcriptional,posttranscriptional,translational,and epigenetic levels.N^(6)-methyladenosine(m^(6)A)is a highly evolutionarily conserved epigenetic modification in mammals.The m^(6)A modification is commonly linked to tumor proliferation,progression,and therapy resistance because it is involved in RNA metabolic processes.Intriguingly,accumulating evidence suggests that dysregulated ferroptosis caused by the m^(6)A modification drives tumor development.In this review,we summarized the roles of m^(6)A regulators in ferroptosis-mediated malignant tumor progression and outlined the m^(6)A regulatory mechanism involved in ferroptosis pathways.We also analyzed the potential value and application strategies of targeting m^(6)A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.

The Dual Effects of Interleukin-18 in Tumor Progression

Interleukin-18 （IL-18） was discovered as an interferon-y-inducing factor and had a critical role in inflammatory and immune respouse. It stimulates natural killer （NK） and T cells and enhances Thl immune response. These activated immune cells eliminate cancer cells and virus-infected cells effectively. However, IL-18 has also been found to promote tumor progression. Higher expression or secretion level of IL-18 is detected in various cancer cells in comparison with normal control, and IL-18 is able to induce angiogenesis, migration/metastasis, proliferation and immune escape. These dual effects and the mechanism of IL-18 need to be investigated further as it relates to cancer.

RNA editingof SLC22A3 causes early tumor progression in familial esophageal cancer patients

Subject Code:H16With the support by the National Natural Science Foundation of China,a collaborative study by the Research groups led by Prof.Fu Li(付利)from the Cancer Research Center,Shenzhen University School of Medicine and Prof.Guan Xinyuan(关新元)from the University of Hong Kong reported that an

The role and research progress of MDSC in immune aging-related diseases

Myeloid-derived suppressor cells(MDSCs)are a group of heterogeneous immature cells with a strong immunosuppressive function in myeloid cells,which are impeded in the differentiation of myeloid cells under the pathological conditions of hypoxia,inflammation,infection,and cancer.As individuals age,there is a significant increase in myeloid-derived suppressor cells(MDSCs),which subsequently enhance the immunosuppressive functions of Tregs(regulatory T cells)and Bregs(regulatory B cells).Therefore,MDSC may be related to immune system remodeling,thereby preventing excessive lesions caused by aging.This indicates that MDSC could serve as a potent inducer of immune senescence.Immune senescence,characterized by immune dysfunction with aging,is closely linked to the onset of diseases like infections,pulmonary fibrosis,and tumors.To achieve the purpose of anti-aging by intervening in immune aging and slow down the occurrence and development of related diseases.Therefore,understanding the biological characteristics of MDSC and its role in immune aging is crucial for immunotherapy targeting MDSC.This article reviews the different roles of MDSC in immune aging and its relationship with pulmonary fibrosis,tumor and other related diseases to provide theoretical basis for more comprehensive targeted MDSC immunotherapy.

Oncoprotein HBXIP promotes tumorigenesis through MAPK/ERK pathway activation in non-small cell lung cancer

Objective:The oncoprotein,hepatitis B X-interacting protein(HBXIP),has been reported to play an important role in human malignancies.However,its functions in non-small cell lung cancer(NSCLC)are poorly understood.The goal of the present study was to identify the role of HBXIP in the regulation of NSCLC development.Methods:The level of HBXIP expression in NSCLC tissue was assessed by immunohistochemical and Western blot analyses,and its relationships with clinicopathological features and outcomes were statistically evaluated.The effects of HBXIP on NSCLC cell progression were assessed through cell viability,colony formation,and flow cytometry analyses in vitro.The mechanism by which HBXIP regulated the MAPK pathway was studied by Western blot,immunofluorescence,and immunoprecipitation assays.In addition,in vivo experiments were performed to evaluate the progression of NSCLC and ERK signaling pathway activation after HBXIP knockdown.Results:HBXIP was overexpressed in human NSCLC and was correlated with the invasiveness of NSCLC.The high expression of HBXIP in NSCLC was significantly correlated with gender(P=0.033),N stage(P=0.002),and tumor-node-metastasis stage(P=0.008).In vitro experiments using an NSCLC cell line revealed that HBXIP knockdown resulted in the suppression of cell proliferation and colony formation,which was consistent with the enhanced cell cycle arrest in G1 phase.The results of a mechanistic investigation suggested that binding of HBXIP to MEK1 protein promoted MAPK/ERK signaling pathway activation in NSCLC by preventing the proteasome-mediated degradation of MEK1.In addition,the results obtained using in vivo subcutaneous tumor xenografts confirmed that HBXIP deficiency decreased MEK1 protein levels and NSCLC tumor growth.Conclusions:Taken together,our results showed that the HBXIP-MEK interaction promoted oncogenesis via the MAPK/ERK pathway,which may serve as a novel therapeutic target for cancers in which MAPK/ERK signaling is a dominant feature.

Role of the mechanical microenvironment in cancer development and progression

Cross-talk between tumor cells and mechanical stress in the tumor microenvironment has been shown to be involved in carcinogenesis.High mechanical stress in tumors can alter the metabolism and behaviors of cancer cells and cause cancer cells to attain cancer stem-like cell properties,thus driving tumor progression and promoting metastasis.The mechanical signal is converted into a biochemical signal that activates tumorigenic signaling pathways through mechanotransduction.Herein,we describe the physical changes occurring during reprogramming of cancer cell metabolism,which regulate cancer stem cell functions and promote tumor progression and aggression.Furthermore,we highlight emerging therapeutic strategies targeting mechanotransduction signaling pathways.

Research advances of secretory proteins in malignant tumors

Secretory proteins in tumor tissues are important components of the tumor microenvironment.Secretory proteins act on tumor cells or stromal cells or mediate interactions between tumor cells and stromal cells,thereby affecting tumor progression and clinical treatment efficacy.In this paper,recent research advances in secretory proteins in malignant tumors are reviewed.

Tumor circulome in the liquid biopsies for digestive tract cancer diagnosis and prognosis

Digestive tract cancer is one of the main diseases that endanger human health.At present,the early diagnosis of digestive tract tumors mainly depends on serology,imaging,endoscopy,and so on.Although tissue specimens are the gold standard for cancer diagnosis,with the rapid development of precision medicine in cancer,the demand for dynamic monitoring of tumor molecular characteristics has increased.Liquid biopsy involves the collection of body fluids via noninvasive approaches,and analyzes biological markers such as circulating tumor cells,circulating tumor DNA,circulating cell-free DNA,microRNAs,and exosomes.In recent years,liquid biopsy has become more and more important in the diagnosis and prognosis of cancer in clinical practice due to its convenience,non-invasiveness,high specificity and it overcomes temporal-spatial heterogeneity.Therefore,this review summarizes the current evidence on liquid biopsies in digestive tract cancers in relation to diagnosis and prognosis.

RNF43 is a novel tumor-suppressor and prognostic indicator in clear cell renal cell carcinoma

Identifying prognostic indicators of clear cell renal cell carcinoma(ccRCC)and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis.This study investigated the clinical significance and biological role of Ring finger protein 43(RNF43)in ccRCC.Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses.In vitro and in vivo experiments,RNA-seq,and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms.RNF43 expression was commonly decreased in ccRCC specimens,and low expression of RNF43 indicated a higher TNM stage,SSIGN score,and WHO/ISUP grade and short survival in patients with ccRCC.Additionally,RNF43 overexpression suppressed the proliferation,migration,and targeted drug resistance of ccRCC cells,while the knockdown of RNF43 enhanced these characteristics of ccRCC.RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP.By contrast,RNF43 overexpression showed the opposite effects.Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC.Additionally,restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC.Furthermore,combining the expression of RNF43 and YAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients.In summary,our study identified a novel tumor suppressor,RNF43,which is also a prognostic indicator and potential target for ccRCC.

Oncological outcomes and predictors of radiofrequency ablation of colorectal cancer liver metastases

BACKGROUND Surgical resection is considered the standard treatment option for long-term survival in colorectal cancer liver metastasis(CRLM)patients,but only a small number of patients are suitable for resection following diagnosis.Radiofrequency ablation(RFA)is an accepted alternative therapy for CRLM patients who are not suitable for resection.However,the relatively high rate of local tumor progression(LTP)is an obstacle to the more widespread use of RFA.AIM To determine the oncological outcomes and predictors of RFA in CRLM patients.METHODS A retrospective analyze was performed on the clinical data of 85 consecutive CRLM patients with a combined total of 138 liver metastases,who had received percutaneous RFA treatment at our institution from January 2013 to December 2018.Contrast-enhanced computed tomography was performed the first month after RFA to assess the technique effectiveness of the RFA and to serve as a baseline for subsequent evaluations.The Kaplan-Meier method was used to calculate overall survival(OS)and LTP-free survival(LTPFS).The log-rank test and Cox regression model were used for univariate and multivariate analyses to determine the predictors of the oncological outcomes.RESULTS There were no RFA procedure-related deaths,and the technique effectiveness of the treatment was 89.1%(123/138).The median follow-up time was 30 mo.The LTP rate was 32.6%(45/138),and the median OS was 36 mo.The 1-,3-,and 5-year OS rates were 90.6%,45.6%,and 22.9%,respectively.Univariate analysis revealed that tumor size and ablative margin were the factors influencing LTPFS,while extrahepatic disease(EHD),tumor number,and tumor size were the factors influencing OS.Multivariate analysis showed that tumor size larger than 3 cm and ablative margin of 5 mm or smaller were the independent predictors of shorter LTPFS,while tumor number greater than 1,size larger than 3 cm,and presence of EHD were the independent predictors of shorter OS.CONCLUSION RFA is a safe and effective treatment method for CRLM.Tumor size and ablative margin are the important factors affecting LTPFS.Tumor number,tumor size,and EHD are also critical factors for OS.

Neurotrophin 3 hinders the growth and metastasis of hepatocellular carcinoma cells

Objective Neurotrophin 3(NTF3)is involved in numerous biological processes;however,its role in hepatocellular carcinoma(HCC)is not well studied.This study investigated NTF3 function in HCC progression and revealed its underlying molecular mechanisms.Methods The prognostic relevance of NTF3 was determined through a bioinformatical analysis of publicly available TCGA data.Immunohistochemistry of HCC biopsies was performed to explore the expression of NTF3.Cell growth and proliferation were analyzed using a Cell Counting Kit-8(CCK-8)assay.Cell invasion and migration were analyzed using Boyden Transwell and wound healing assays.Protein expression and mRNA levels were evaluated through immunoblotting and quantitative polymerase chain reaction(qPCR).Cell apoptosis was evaluated with flow cytometry.Results NTF3 expression was significantly lower in HCC tissues than in adjacent non-tumor tissues.Low NTF3 expression was significantly associated with decreased patient survival and specific clinicopathological features.NTF3 overexpression reduced the proliferation,migration,and invasion abilities of HCC cell lines.Conclusion Decreased expression of NTF3 is associated with poor prognosis in HCC patients,likely due to its action in promoting HCC cell proliferation,migration,and invasion.Our findings provide a novel understanding into the pathogenesis of HCC and the role of NTF3 in tumor progression,suggesting that targeting NTF3 has potential therapeutic and diagnostic value for HCC.

Multiple subcellular localizations and functions of protein kinase Cδ in liver cancer

Protein kinase Cδ(PKCδ)is a member of the PKC family,and its implications have been reported in various biological and cancerous processes,including cell proliferation,cell death,tumor suppression,and tumor progression.In liver cancer cells,accumulating reports show the bi-functional regulation of PKCδin cell death and survival.PKCδfunction is defined by various factors,such as phosphorylation,catalytic domain cleavage,and subcellular localization.PKCδhas multiple intracellular distribution patterns,ranging from the cytosol to the nucleus.We recently found a unique extracellular localization of PKCδin liver cancer and its growth factor-like function in liver cancer cells.In this review,we first discuss the structural features of PKCδand then focus on the functional diversity of PKCδbased on its subcellular localization,such as the nucleus,cell surface,and extracellular space.These findings improve our knowledge of PKCδinvolvement in the progression of liver cancer.

Efficacy and safety of computed tomography-guided microwave ablation with fine needle-assisted puncture positioning technique for hepatocellular carcinoma

BACKGROUND In microwave ablation(MWA), although computed tomography(CT) scanning can overcome gas interference, it cannot achieve real-time localization. Therefore, the puncture technique is more important in CT-guided ablation.AIM To compare the fine needle-assisted puncture(FNP) positioning technique and the conventional puncture(CP) technique for the safety and efficacy of CT-guided MWA in treating hepatocellular carcinoma(HCC).METHODS This retrospective study included 124 patients with 166 tumor nodules from February 2018 and June 2021. Seventy patients received CT-guided MWA under the FNP technique(FNP group), and 54 patients received MWA under the CP technique(CP group). Intergroup comparisons were made regarding local tumor progression(LTP), recurrence-free survival(RFS), overall survival(OS), and complications. The influencing variables of LTP and RFS were analyzed through univariate and multivariate regressions.RESULTS The 1-, 2-, and 3-year cumulative incidences of LTP in the FNP group were significantly lower than those in the CP group(7.4%, 12.7%, 21.3% vs 13.7%, 32.9%, 36.4%;P = 0.038). The 1-, 2-, and 3-year RFS rates in the FNP group were significantly higher than those in the CP group(80.6%, 73.3%, 64.0% vs 83.3%,39.4%, and 32.5%, respectively;P = 0.008). The FNP technique independently predicted LTP and RFS. Minor complications in the FNP group were lower than those in the CP group(P < 0.001). The difference in median OS was insignificant between the FNP and CP groups(P = 0.229).CONCLUSION The FNP technique used in CT-guided MWA may improve outcomes in terms of LTP, RFS, and procedure-related complications for HCC.

Myeloid-derived suppressor cells in gastrointestinal cancers:A systemic review

Gastrointestinal(GI)cancers are one of the most common malignancies worldwide,with high rates of morbidity and mortality.Myeloid-derived suppressor cells(MDSCs)are major components of the tumor microenvironment(TME).MDSCs facilitate the transformation of premalignant cells and play roles in tumor growth and metastasis.Moreover,in patients with GI malignancies,MDSCs can lead to the suppression of T cells and natural killer cells.Accordingly,a better understanding of the role and mechanism of action of MDSCs in the TME will aid in the development of novel immune-targeted therapies.

Clinical Significance of METTL Family Molecules in Hepatocellular Carcinoma

Objective:to search for hepatocellular carcinoma(HCC)in tumor subdivision from different aspects,such as transcripts,proteins,gene mutations,protein interactions,signal pathways and functions.To explore the correlation between METTL1-6 protein family and hepatocellular carcinoma(HCC),and to determine whether METTL family proteins are valuable as potential biomarkers for tumor progression and prognosis of HCC.Methods:We try to use data collection technique to extract the data needed in medical analysis.The correlation between the MRNA expression level of METTL family proteins and the prognosis of HCC patients was obtained from TCGA data.METTL data and clinical data of protein METTL family in tissue samples of HCC patients were obtained from Kaplan-Meier Plotter database for correlation analysis.The immunohistochemical data of METTL family protein 1,2A,2B,3,4,5,6 in normal liver tissue and HCC tissue were obtained from TIMER database.The protein network of METTL proteome was obtained by using STRING database,and the heat map enrichment analysis of proteome interaction between KEGG and GO was done by software.Results:6 of the 7 METTL protein members were highly expressed in HCC tissues,and were positively correlated with the grade and clinical analysis of HCC tumors.

Clinical implications of endogenous testosterone density on prostate cancer progression in patients with very favorable low and intermediate risk treated with radical prostatectomy

We tested the association between endogenous testosterone density(ETD;the ratio between endogenous testosterone[ET]and prostate volume)and prostate cancer(PCa)aggressiveness in very favorable low-and intermediate-risk PCa patients who underwent radical prostatectomy(RP).Only patients with prostate-specific antigen(PSA)within 10 ng ml^(-1),clinical stage T1c,and International Society of Urological Pathology(IsUP)grade group 1 or 2 were included.Preoperative ET levels up to 350 ng dl^(-1)were classified as abnormal.Tumor quantitation density factors were evaluated as the ratio between percentage of biopsy-positive cores and prostate volume(biopsy-positive cores density,BPCD)and the ratio between percentage of cancer invasion at final pathology and prostate weight(tumor load density,TLD).Disease upgrading was coded as ISUP grade group>2,and progression as recurrence(biochemical and/or local and/or distant).Risk associations were evaluated by multivariable Cox and logistic regression models.Of 320 patients,151(47.2%)had intermediate-risk PCa.ET(median:402.3 ng dl^(-1))resulted abnormal in 111(34.7%)cases(median ETD:9.8 ng dl^(-1)ml^(-1)).Upgrading and progression occurred in 109(34.1%)and 32(10.6%)cases,respectively.Progression was predicted by ISUP grade group 2(hazard ratio[HR]:2.290;P=0.029)and upgrading(HR:3.098;P=0.003),which was associated with ISUP grade group 2(odds ratio[OR]:1.785;P=0.017)and TLD above the median(OR:2.261;P=0.001).After adjustment for PSAdensity and bodymass index(BMI),ETDabovethemedianwas positivelyassociatedwithBPCD(OR:3.404;P<0.001)and TLD(OR:5.238;P<0.001).Notably,subjects with abnormal ET were more likely to have higher BPCD(OR:5.566;P=0.002),as well as TLD(OR:14.998;P=0.016).Independently by routinely evaluated factors,as ETD increased,BPCD and TLD increased,but increments were higher for abnormal ET levels.In very favorable cohorts,ETD may further stratify the risk of aggressive PCa.

Dynamic heterogeneity of colorectal cancer during progression revealed clinical risk-associated cell types and regulations in single-cell resolution and spatial context

Background:Tumor heterogeneity is contributed by tumor cells and the microenvironment.Dynamics of tumor heterogeneity during colorectal cancer(CRC)progression have not been elucidated.Methods:Eight single-cell RNA sequencing(scRNA-seq)data sets of CRC were included.Milo was utilized to reveal the differential abundance of cell clusters during progression.The differentiation trajectory was imputed by using the Palantir algorithm and metabolic states were assessed by using scMetabolism.Three spatial transcription sequencing(ST-seq)data sets of CRC were used to validate cell-type abundances and colocalization.Cancer-associated regulatory hubs were defined as communication networks affecting tumor biological behaviors.Finally,quantitative reverse transcription polymerase chain reaction and immunohistochemistry staining were performed for validation.Results:TM4SF1t,SOX4t,and MKI67t tumor cells;CXCL12t cancer-associated fibroblasts;CD4t resident memory T cells;Treg;IgAt plasma cells;and several myeloid subsets were enriched in stage IV CRC,most of which were associated with overall survival of patients.Trajectory analysis indicated that tumor cells from patients with advanced-stage CRC were less differentiated,when metabolic heterogeneity showed a highest metabolic signature in terminal states of stromal cells,T cells,and myeloid cells.Moreover,ST-seq validated cell-type abundance in a spatial context and also revealed the correlation of immune infiltration between tertiary lymphoid structures and tumors followed by validation in our cohort.Importantly,analysis of cancer-associated regulatory hubs revealed a cascade of activated pathways including leukocyte apoptotic process,MAPK pathway,myeloid leukocyte differentiation,and angiogenesis during CRC progression.Conclusions:Tumor heterogeneity was dynamic during progression,with the enrichment of immunosuppressive Treg,myeloid cells,and fibrotic cells.The differential state of tumor cells was associated with cancer staging.Assessment of cancer-associated regulatory hubs suggested impaired antitumor immunity and increased metastatic ability during CRC progression.

Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer

Background:Triple-negative breast cancer(TNBC)is an aggressive type of breast cancer associated with poor prognosis and limited treatment options.The androgen receptor(AR)has emerged as a potential therapeutic target for luminal androgen receptor(LAR)TNBC.However,multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits.This study aimed to investigate the role of AR in TNBC and its detailed mechanism.Methods:Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4(NECTIN4)expression in TNBC tissues.Then,in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta(ERβ)in TNBC.Chromatin immunoprecipitation sequencing(ChIP-seq),co-immunoprecipitation(co-IP),molecular docking method,and luciferase reporter assay were performed to identify key molecules that affect the function of AR.Results:Based on the TNBC tissue array analysis,we revealed that ERβand AR were positive in 21.92%(32/146)and 24.66%(36/146)of 146 TNBC samples,respectively,and about 13.70%(20/146)of TNBC patients were ERβpositive and AR positive.We further demonstrated the pro-tumoral effects of AR on TNBC cells,however,the oncogenic biology was significantly suppressed when ERβtransfection in LAR TNBC cell lines but not in AR-negative TNBC.Mechanistically,we identified that NECTIN4 promoter–42 bp to–28 bp was an AR response element,and that ERβinteracted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression.Conclusions:This study suggests that ERβfunctions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation.Therefore,our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.