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Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA m

Immunotherapy has achieved limited success in patients with triple-negative breast cancer (TNBC), an aggressive disease with a poor prognosis. Commensal microbiota have been proven to colonize the mammary gland, but whether and how they modulate the tumor microenvironment remains elusive. We performed a multiomics analysis of a cohort of patients with TNBC (n = 360) and found genera under Clostridiales, and the related metabolite trimethylamine N-oxide (TMAO) was more abundant in tumors with an activated immune microenvironment. Patients with higher plasma TMAO achieved better responses to immunotherapy. Mechanistically, TMAO induced pyroptosis in tumor cells by activating the endoplasmic reticulum stress kinase PERK and thus enhanced CD8

Immune checkpoint inhibitor (ICI) therapy is generating remarkable responses in individuals with cancer, but only a small portion of individuals with breast cancer respond well. Here we report that tumor-derived Jagged1 is a key regulator of the tumor immune microenvironment. Jagged1 promotes tumorigenesis in multiple spontaneous mammary tumor models. Through Jagged1-induced Notch activation, tumor cells increase expression and secretion of multiple cytokines to help recruit macrophages into the tumor microenvironment. Educated macrophages crosstalk with tumor-infiltrating T cells to inhibit T cell proliferation and tumoricidal activity. In individuals with triple-negative breast cancer, a high expression level of Jagged1 correlates with increased macrophage infiltration and decreased T cell activity. Co-administration of an ICI PD-1 antibody with a Notch inhibitor significantly inhibits tumor growth in breast cancer models. Our findings establish a distinct signaling cascade by which Jagged1 promotes adaptive immune evasion of tumor cells and provide several possible therapeutic targets.

Triple-negative breast cancer (TNBC) is a subset of breast cancer with adverse prognosis and significant tumor heterogeneity. Here, we used MRI images from a breast cancer cohort consisting of 860 patients to construct a radiomic signature that could identify TNBC with an AUC of 0.92 (95% CI: 0.887 to 0.953) and validated in another cohort. Moreover, we developed radiomic signatures to distinguish TNBC subtypes with moderate efficacy. Furthermore, we identified peritumoral dependence nonuniformity of the gray level dependence matrix, which captures the intratumor heterogeneity in the tumor boundary, as the most significant prognostic factor (P = 0.04 for recurrence-free survival and P = 0.02 for overall survival). The integration of transcriptomic and metabolomic data indicated that high peritumor heterogeneity was related to immune suppression and enhanced metabolism. Our findings suggest that radiomics data can serve as a noninvasive predictor for molecular subtyping and clinical outcome in patients with TNBC.

PurposeRegulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.Experimental designUsing the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.ResultsWe revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.ConclusionsTumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and patients with early-stage TNBCs have distinct likelihood of distant recurrence. Methods: In this study, We extracted transcriptome data for 189 pathologically confirmed pT1-2 node-negative TNBC patients at Fudan University Shanghai Cancer Center. Candidate mRNAs were filtered, which was followed by differential expressed mRNAs analysis, survival analysis, and LASSO Cox regression model. All-subsets regression program was used for constructing a multi-mRNA signature in the training set (n=159); the accuracy and prognostic value were then validated using an independent validation set (n=158). Results: Here, we profiled the transcriptome data from 189 early-stage TNBC patients along with 50 paired normal tissues, and developed a prognostic signature based on seven mRNAs (ACAN, KRT5, TMEM101, LCA5, RPP40, LAGE3, CDKL2).In both the training (n=159) and validation cohorts (n=158), the signature could identify patients with relatively high recurrence risks and serve as an independent prognostic factor. Furthermore, the signature had better prognostic value than traditional clinicopathological features in both sets. Among the seven mRNAs, TMEM101 was identified as a prognostic biomarker of early-stage TNBC. Additional cell experiments suggested that TMEM101 could facilitate migration and proliferation of TNBC cells. Conclusions: Our 7-mRNA signature could accurately predict recurrence risks of early-stage TNBCs. Clinical and genomic low risk TNBC patients may safely avoid adjuvant chemotherapy.

BACKGROUND: Controversy remains regarding the predictive and prognostic value of serum human epidermal growth factor receptor 2 (HER2) in breast cancer. The purpose of this retrospective study was to determine the clinical utility and efficacy of serum HER2 (sHER2) in predicting treatment response and prognosis in patients with HER2-positive breast cancer undergoing neoadjuvant chemotherapy and trastuzumab treatment. METHODS: A total of 309 HER2-positive breast cancer patients diagnosed at Fudan University Shanghai Cancer Center from July 2015 to January 2019 were analyzed. Baseline sHER2 levels were obtained for all patients and sHER2 levels were collected after 2 cycles of treatment in 208 patients. A sHER2 level ≥15 ng/mL was regarded as “high expression” and sHER2

The Pax7+ muscle stem cells (MuSCs) are essential for skeletal muscle homeostasis and muscle regeneration upon injury, while the molecular mechanisms underlying muscle stem cell fate determination and muscle regeneration are still not fully understood. N6-methyladenosine (m6A) RNA modification is catalyzed by METTL3 and plays important functions in posttranscriptional gene expression regulation and various biological processes. Here, we generated muscle stem cell-specific METTL3 conditional knockout mouse model and revealed that METTL3 knockout in muscle stem cells significantly inhibits the proliferation of muscle stem cells and blocks the muscle regeneration after injury. Moreover, knockin of METTL3 in muscle stem cells promotes the muscle stem cell proliferation and muscle regeneration in vivo. Mechanistically, METTL3-m6A-YTHDF1 axis regulates the mRNA translation of Notch signaling pathway. Our data demonstrated the important in vivo physiological function of METTL3-mediated m6A modification in muscle stem cells and muscle regeneration, providing molecular basis for the therapy of stem cell-related muscle diseases.

Nonalcoholic steatohepatitis (NASH) is a dramatically growing indication for liver transplantation (LT) worldwide and the posttransplant outcomes of NASH patients are currently under intensive investigation. This quantitative meta-analysis aimed to update the clinical evidence on outcomes of transplanted patients with NASH.We performed a systematic review and meta-analysis of studies (published up to September 15, 2021) that focused on LT outcomes for NASH versus non-NASH patients. Random-effect meta-analysis was conducted to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses based on crucial baseline clinical characteristics and leave-one-out sensitivity analyses were conducted to assess the robustness of the pooled results. Meta-regression was used to evaluate study-level demographic, clinical, and biochemical characteristics to identify potential confounders affecting patient survival.Twenty-two non-randomized comparative studies with 1,538 NASH and 6,014 non-NASH patients were included. 1- (OR, 0.94; 95% CI, 0.77-1.14), 3- (OR, 0.82; 95% CI, 1.00-1.22), and 5- (OR, 1.05; 95% CI, 0.84-1.31) year patient survival was equivalent between NASH and non-NASH recipients. NASH patients were associated with similar cardiovascular mortality (OR, 1.36; 95% CI, 0.89-2.09) and retransplantation rates (OR, 0.69; 95% CI, 1.03-1.53), lower graft failure-related mortality (OR, 0.11; 95% CI, 0.29-0.74), but higher sepsis-related mortality (OR, 1.53; 95% CI, 1.13-2.06). Meta-regression revealed that a higher proportion of patients with hepatocellular carcinoma (HCC) were associated with significantly superior overall patient survival at 1 (P = 0.044), 3 (P = 0.035) and 5 (P = 0.049) years after LT in NASH compared with non-NASH.This study shows no difference in posttransplant survival between NASH and non-NASH patients. Carefully selected patients with NASH-related HCC may benefit from LT. NASH recipients should be managed with caution posttransplant, especially regarding the potentially high risk of sepsis-related death.

Background: Molecular stratification and tailored target therapy bring clinical benefit for patients with triple-negative breast cancer (TNBC), but it is difficult to implement comprehensive molecular testing in clinical practice. Thus, we aim to devise an approach based on digital pathology and deep learning for the molecular and prognostic stratification of TNBC. Methods: We collected digital whole slide images (WSIs) (N=425) of our previously established TNBC cohort with multi-omics data. A deep learning-based workflow was developed and applied to these WSIs to train and validate neural network models to predict multi-omics molecular features, to identify molecular subtypes, and to improve prognostic evaluation. The models that showed high prediction accuracy were further validated on the TNBC cases from TCGA (N=143). Findings: A model was first developed for automatic tissue type classification, which enabled selection of certain tissue types on WSIs for the following prediction. Numerous molecular features can be inferred from WSIs including the somatic PIK3CA mutation, germline BRCA2 mutation and PD-L1 expression. All of the four molecular subtypes of TNBC can be accurately identified based on WSIs and distinctive morphological patterns were revealed for each subtype. The addition of image features to clinical prognostic factors significantly improved the accuracy of relapse risk assessment. The models for predicting PIK3CA mutation, PD-L1 expression, TNBC subtypes and relapse risk can be well generalized to the TCGA TNBC cases. The complete prediction workflow along with validated models was modularized and deployed on an online platform, which can realize real-time one-stop prediction for newly-uploaded WSIs. Interpretation: We proposed a deep learning-based workflow and developed neural network models to predict clinically relevant information of TNBC from pathological WSIs. Our findings and established platform may enable the implementation of artificial intelligence guided precision treatment in clinical trials and future routine practice. Funding: Fudan University Shanghai Cancer Center. Declaration of Interest: None to declare Ethical Approval: The tissue samples used in our study were obtained after the approval from the FUSCC Ethics Committee.

Mesenchymal stemXin cells (MSCs) are a great cell source for bone regeneration. Although combining MSCs with growth factors and scaffolds provides a useful clinical strategy for bone tissue engineering, the efficiency of MSC osteogenic differentiation remains to be improved. Epigenetic modification is related to the differentiation ability of MSCs during osteogenic induction. In this study, we evaluate the effect of Chaetocin, an inhibitor of lysine-specific histone methyltransferases, on the differentiation of MSCs. We found that MSCs treated with Chaetocin demonstrated increased osteogenic ability and reduced adipogenic ability. The expression of osteogenic markers (Runx2 and OPN) was induced in MSCs by Chaetocin during osteogenic induction. Moveover, treatment of Chaetocin in MSCs improves Wnt/β-catenin signaling pathways and its downstream targets. Finally, we showed increased bone formation of MSC and Wnt/β-catenin signaling activity by treatment of Chaetocin using in vivo bone formation assays. Our data uncovered a critical role of Chaetocin in MSC osteogenic differentiation and provide new insights into bone tissue regeneration and repair.

Background The germline variant spectrum of triple-negative breast cancer (TNBC) is different from that of other subtypes and has demonstrated ethnic differences. However, the germline variants of TNBC among Chinese patients and its clinical significance remain unclear. Methods Using our multi-omics TNBC cohort (n = 325), we determined the spectrum of germline variants in TNBC and aimed to illustrate their biological and clinical implications. Results Overall, 16.0% (52 of 325) of TNBC patients harbored at least 1 pathogenic or likely pathogenic germline variant. These germline variants were associated with early onset of TNBC, the occurrence of contralateral breast cancer, the basal-like immune-suppressed mRNA subtype, and the homologous recombination deficiency (HRD) mutation subtype. Somatic allele-specific imbalance was observed in 54.1% of these germline variants, which was correlated with early onset of breast cancer and elevated HRD. The genes BRCA1 (7.4%), RAD51D (2.8%), and BRCA2 (2.2%) were those most frequently mutated. The RAD51D germline variants, especially K91fs, were enriched in Chinese patients with TNBC compared with Caucasian and African American patients. The Chinese-specific RAD51D germline variants were functionally associated with the instability of the RAD51D protein, HRD, and sensitivity to PARP inhibitors. Conclusions Chinese TNBC patients have a distinct spectrum of germline variants, with a remarkable impact on the clinical and molecular characteristics of the tumor. Integrative germline-somatic analysis may help identify TNBC patients who are most likely to be affected by their germline variants and in performing clinical interventions more precisely. The RAD51D variants enriched in our cohort may serve as therapeutic targets and guide precision treatment of TNBC.

Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.

Nanopore-based DNA sequencing technology has become one of the most promising sequencing approaches with its advantages of label-free and low cost. However, most of the biosensor systems for nanopore sequencing only perform passive detection which is merely part of the overall function of a practical DNA sequencing platform. In this paper, a multifunctional automated integrated CMOS platform for nanopore-based DNA sequencing is presented. The platform equipped with 16∗8 biosensor array for nanopore detection is also able to perform bilayer lipid membrane capacitance detection and nanopore insertion pulse generation, realizing the whole process automated auxiliary function from transducer preparation to DNA sequencing. Post layout simulation shows that each cell consumes only 37.366μW while the whole system occupying 1.633mm2.

Background-objectives: Liver transplantation (LT) and combined liver and kidney transplantation (CLKT) have been proposed as enzyme replacement therapies for methylmalonic aciduria (MMA). We aimed to synthesize the available evidence on their safety and efficacy. Methods: Medline, Embase and Cochrane library were searched to identify studies that reported post-LT/CLKT clinical outcomes of MMA from their inception to February 1, 2020. The pooled rate was calculated using random-effects model with Freeman–Tukey double arcsine transformation method. Results: Thirty-two studies involving 109 patients were included. The pooled estimate rates were 99.9% (95% CI 95.3–100.0) for patient survival, 98.5% (95% CI 91.5–100.0) for graft survival after LT/CLKT. The combined incidence of biliary, vascular complications and rejection were 0.2% (95% CI 0.0–6.6), 7.7% (95% CI 0.1–22.1) and 18.4% (95% CI 4.6–36.3), respectively. The pooled estimate rates were 100.0% (95% CI 99.4–100.0) for metabolic eradication, 61.5% (95% CI: 33.4–87.0) for normalization of kidney function. Chronic kidney disease (CKD) remission is more promising after CLKT (70.3% VS 37.6% in LT group). The pooled estimate rates for neurodevelopmental status improvement and protein intake liberalization were 52.0% (95% CI 2.8–98.8) and 36.3% (95% CI 6.3–71.7), respectively. Conclusions: This first quantitative systematic review confirms favorable survival outcomes and partially improved disease-related complications in transplanted MMA patients, although some results should be interpreted with caution. Future studies with detailed description of long-term outcomes and consensus on neurodevelopmental evaluation method can help provide a more accurate picture.

Progression of triple-negative breast cancer (TNBC) constitutes a major unresolved clinical challenge, and effective targeted therapies are lacking. Because microtubule dynamics play pivotal roles in breast cancer metastasis, we performed RNA sequencing on 245 samples from TNBC patients to characterize the landscape of microtubule-associated proteins (MAPs). Here, our transcriptome analyses revealed that low expression of one MAP, tektin4, indicated poor patient outcomes. Tektin4 loss led to a marked increase in TNBC migration, invasion, and metastasis and a decrease in microtubule stability. Mechanistically, we identified a novel microtubule-associated complex containing tektin4 and histone deacetylase 6 (HDAC6). Tektin4 loss increased the interaction between HDAC6 and α-tubulin, thus decreasing microtubule stability through HDAC6-mediated tubulin deacetylation. Significantly, we found that tektin4 loss sensitized TNBC cells, xenograft models, and patient-derived organoid models to the HDAC6-selective inhibitor ACY1215. Furthermore, tektin4 expression levels were positively correlated with microtubule stability levels in clinical samples. Together, our findings uncover a metastasis suppressor function of tektin4 and support clinical development of HDAC6 inhibition as a new therapeutic strategy for tektin4-deficient TNBC patients.

Resistance to paclitaxel remains a major challenge in treating breast cancer. Our preclinical study suggested that TEKT4 germline variations in breast cancer are associated with paclitaxel resistance and increase vinorelbine sensitivity. This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy. In this open-label, single-center, phase II trial, female patients with human epidermal growth factor receptor 2 (HER2)-negative, stage IIB–IIIC breast cancer harboring TEKT4 germline variations were randomly assigned to the paclitaxel plus epirubicin (PE) or vinorelbine plus epirubicin (NE). The primary endpoint was the pathologic complete response (pCR) rate, and the secondary endpoints were the objective response rate (ORR) and safety. Targeted sequencing of a panel comprising 484 breast-related genes was performed to identify pCR-associated somatic mutations in each group. 91 Patients were assigned to PE (46 patients) or NE (45 patients). NE numerically increased the pCR rate (22.2% versus 8.7%, P = 0.074). The ORRs for NE and PE were 82.2% and 76.1%, respectively. Interestingly, NE (15.4%) showed a significantly higher pCR rate than PE (0%) in the hormone receptor (HR)-positive subgroup (P = 0.044). Both regimens were well tolerated, with grade 3 and 4 toxicities reported at the expected levels. The biomarker analysis showed that UNC13D mutation predicted the pCR rate in NE (P = 0.011). Although the primary endpoint was not met, NE might bring clinical benefit to HR-positive patients or patients simultaneously carrying UNC13D mutations.

Background Patients with isolated methylmalonic acidemia (MMA) usually experience recurrent episodes of acute metabolic decompensation or metabolic stroke, require frequent hospitalization, and have a relatively high mortality rate. The aim of our study was to assess factors predicting the in-hospital death of pediatric patients with isolated MMA. We performed a retrospective study using data from the Hospital Quality Monitoring System, a national inpatient database in China collected from 2013 to 2017. All patients under 18 years old with a diagnosis of isolated MMA were included. Demographic, hospital-related, and clinical features were collected. Poisson regression was performed to identify potential influencing variables associated with in-hospital death. Results From 2013 to 2017, among 2317 admissions for pediatric patients diagnosed with isolated MMA, 1.77% had the outcome of death. In the univariate analysis, patients aged under 1 year had a higher risk of death than did those aged 1 year or older (odds ratio [OR] = 2.63, 95% confidence interval [CI]: 1.36–5.07). There was a higher risk of in-hospital death for patients admitted through emergency departments or via referrals than for those admitted through other routes (OR = 3.76, 95% CI: 1.84–7.67). Deaths were higher in hospitals with volumes of less than 50 patients with isolated MMA during the five study years (OR = 2.92, 95% CI: 1.46–5.83). Moreover, the risk of in-hospital death gradually decreased over time (OR = 0.72, 95% CI: 0.57–0.90). In the multivariate analysis, the abovementioned associations with the risk of in-hospital death remained statistically significant. However, no significant associations were observed between specific clinical signs and in-hospital death in either the univariate or the multivariate analysis. Conclusions Younger age, admission to hospitals with low patient volumes, and admission through emergency departments or referrals are associated with higher risk of in-hospital death. The co-existence of specific clinical signs appears to have no effect on in-hospital death.

BACKGROUND: Various sonographic features of triple-negative invasive breast carcinomas (TNBC) expected to be associated with the molecular subtypes based on transcriptomic analysis were examined. The effects of clinical, sonographic, pathological, and molecular features on survival outcome was also studied. METHODS: One hundred and fourteen patients with breast cancer with negative expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal receptor 2 (HER2) were included in our retrospective study. Based on the transcriptomic profiles, four stable clusters named immunomodulatory (IM), luminal androgen receptor (LAR), mesenchymal-like (MES), and basal-like and immune-suppressed (BLIS) were identified. Ultrasound (US) images were reviewed by two US physicians according to Breast Imaging Reporting and Data System (BI-RADS). Multivariate Cox regression was used to determine the variables associated with recurrence-free survival (RFS) and overall survival (OS). RESULTS: There were 21 IM, 18 LAR, 36 MES, and 39 BLIS cases. The four molecular subtypes showed significant differences in terms of tumor shape (P=0.008) and posterior acoustic pattern (P=0.028). Compared with the subtypes LAR and MES, the IM and BLIS subtypes had higher probability of presenting benign-like sonographic features, such as regular shape, no angular/spiculated margin, and posterior acoustic enhancement (P

Self-healing conductive composites have attracted tremendous interest in recent years due to their many important applications, especially in stretchable and reconfigurable electronics as self-healing electrodes. However, the conductivity of these conductive composite electrodes after healing is limited by the poor capability of the self-healing polymer matrix to move the conductive fillers. Herein, we report a novel stretchable self-healing conductive composite based on a polyborosiloxane (PBS)/polydimethylsiloxane (PDMS) double-network (DN) matrix. The chemically cross-linked PDMS network renders the electrode with good elasticity and mechanical robustness while the non-covalent supramolecular interactions in the PBS network provide it with self-healing and self-adhesive capabilities. Moreover, this DN matrix is able to move not only silver nanowires on the composite surfaces, but also heavier conductive fillers such as silver microflakes embedded inside the bulk due to the highly viscous flow of PBS, yielding a bulk resistivity as low as 0.002 Ω cm and achieving 100% restoration of its original conductivity after damage without any external stimulus. This unique combination of high conductivity, autonomous self-healing of both electrical conductivity and mechanical strength, and self-adhesion may endow the novel composite with a wide range of applications.

Screw mechanism fixing bolt fracture failure of a 500kV circuit breaker spring mechanism running process. By analyzing the installation position and operating environment, and by means of chemical analysis, metallographic examination and other means, the microstructure macro and micro fracture morphology of the fracture bolt were analyzed. The results show that the surface of the bolt is hydrogen-rich and produces hydrogen embrittlement during surface treatment.

Background: Patients with early stage breast cancer with lymph nodes metastasis were proven to have more aggressive biologically phenotypes. This study aimed to build a nomogram to predict lymph node metastasis in patients with T1 breast cancer. Methods: We identified female patients with T1 breast cancer diagnosed between 2010 and 2014 in the Surveillance, Epidemiology and End Results database. The patients were randomized into training and validation sets. Univariate and multivariate logistic regressions were carried out to assess the relationships between lymph node metastasis and clinicopathological characteristics. A nomogram was developed and validated by a calibration curve and receptor operating characteristic curve analysis. Result: Age, race, tumour size, tumour primary site, pathological grade, oestrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER2) status were independent predictive factors of positive lymph node metastasis in T1 breast cancer. Increasing age, tumour size and pathological grade were positively correlated with the risk of lymph node metastasis. We developed a nomogram to predict lymph node metastasis and further validated it in a validation set, with areas under the receiver operating characteristic curves of 0.733 and 0.741 in the training and validation sets, respectively. Conclusions: A better understanding of the clinicopathological characteristics of T1 breast cancer patients might important for assessing their lymph node status. The nomogram developed here, if further validated in other large cohorts, might provide additional information regarding lymph node metastasis. Together with sentinel lymph node biopsy, this nomogram can help comprehensively predict lymph node metastasis.

RNA polymerase II (Pol II)-mediated transcription in metazoans requires precise regulation. RNA Pol II-associated protein 2 (RPAP2) was previously identified to transport Pol II from cytoplasm to nucleus and dephosphorylates Pol II C-terminal domain (CTD). Here, we show that RPAP2 binds hypo-/hyper-phosphorylated Pol II with undetectable phosphatase activity. The structure of RPAP2-Pol II shows mutually exclusive assembly of RPAP2-Pol II and pre-initiation complex (PIC) due to three steric clashes. RPAP2 prevents and disrupts Pol II-TFIIF interaction and impairs in vitro transcription initiation, suggesting a function in inhibiting PIC assembly. Loss of RPAP2 in cells leads to global accumulation of TFIIF and Pol II at promoters, indicating a critical role of RPAP2 in inhibiting PIC assembly independent of its putative phosphatase activity. Our study indicates that RPAP2 functions as a gatekeeper to inhibit PIC assembly and transcription initiation and suggests a transcription checkpoint.

We report a comprehensive proteomic study of a 90-case cohort of paired samples of triple-negative breast cancer (TNBC) in quantification, phosphorylation, and DNA-binding capacity. Four integrative subtypes (iP-1-4) are stratified on the basis of global proteome and phosphoproteome, each of which exhibits distinct molecular and pathway features. Scaffold and co-expression network analyses of three proteomic datasets, integrated with those from genome and transcriptome of the same cohort, reveal key pathways and master regulators that, characteristic of TNBC subtypes, play important regulatory roles within and between scaffold sub-structures and co-expression communities. We find that NAE1 is a potential drug target for subtype iP-1, and a series of key molecules in fatty acid metabolism, such as AKT1/FASN, are plausible targets for subtype iP-2. Libraries of proteins, pathways and networks of TNBC provide a valuable molecular infrastructure for further clinical exploration and in-depth studies of the molecular mechanisms of the disease.

OBJECTIVES To identify clinicopathologic and ultrasound (US) variables that were associated with a heavy nodal tumor burden, which was defined as 3 or more lymph nodes involved with metastasis to the axilla after invasive breast carcinoma. METHODS With ethical approval, 621 patients with a pathologic diagnosis of invasive breast carcinoma were retrospectively analyzed for clinical, pathologic, and US data. Pathologic findings were ascertained by the final paraffin pathologic analysis. Ultrasound characteristics were evaluated on the basis of the American College of Radiology's Breast Imaging Reporting and Data System (BI-RADS). Univariate and multivariate logistic regression analyses were used to assess the clinicopathologic and US variables that were associated with a heavy nodal tumor burden at the axilla. RESULTS There were 107 cases (17.2%) of invasive breast carcinoma with a heavy tumor burden at the axilla. The independent clinicopathologic variables for a heavy tumor burden at the axilla included a tumor size of 2 to 5 cm (odds ratio [OR], 1.86; P = .036), the presence of lymphovascular invasion (OR, 23.52; P

DSCAM‐AS1 is one of the few intensively studied lncRNAs with high specific expression in luminal breast cancer. It is directly regulated by estrogen receptor α (ERα) and plays vital roles in tumor proliferation, invasion, and tamoxifen resistance. However, the detailed function of DSCAM‐AS1 in tumor progression and its clinical significance remain unclear. We reveal that DSCAM‐AS1 regulates cell proliferation and colony formation by inducing the G1/S transition. RNA‐seq analysis demonstrated that DSCAM‐AS1 participates in crucial biological processes, including DNA replication, the G1/S phase transition, sister chromatid cohesion, chromosome segregation, protein localization to the chromosome and DNA recombination. Most importantly, in the retrospectively registered clinical analysis, high expression of DSCAM‐AS1 is a poor prognostic factor in patients with luminal breast cancer treated with endocrine therapy. In conclusion, DSCAM‐AS1 is a promising clinical therapeutic target that may prolong survival of luminal breast cancer patients treated with endocrine therapy.

N6-methyladenosine (m6A) is the most abundant epigenetic modification in eukaryotic mRNAs and is essential for multiple RNA processing events during mammalian development and disease control. Here we show that conditional knockout of the m6A methyltransferase Mettl3 in bone marrow mesenchymal stem cells (MSCs) induces pathological features of osteoporosis in mice. Mettl3 loss-of-function results in impaired bone formation, incompetent osteogenic differentiation potential and increased marrow adiposity. Moreover, Mettl3 overexpression in MSCs protects the mice from estrogen deficiency-induced osteoporosis. Mechanistically, we identify PTH (parathyroid hormone)/Pth1r (parathyroid hormone receptor-1) signaling axis as an important downstream pathway for m6A regulation in MSCs. Knockout of Mettl3 reduces the translation efficiency of MSCs lineage allocator Pth1r, and disrupts the PTH-induced osteogenic and adipogenic responses in vivo. Our results demonstrate the pathological outcomes of m6A mis-regulation in MSCs and unveil novel epitranscriptomic mechanism in skeletal health and diseases., mRNA modifications have been shown to regulate mammalian development and disease. Here the authors show that the m6A methyltransferase Mettl3 ensures translational efficiency of the mesenchymal stem cell lineage allocator Pth1r, promoting osteogenesis and protecting from osteoporosis.

Li-Ping Ge,1,2,* Xi-Yu Liu,1,2,* Yi Xiao,1,2 Zong-Chao Gou,1,2 Shen Zhao,1,2 Yi-Zhou Jiang,1,2 Gen-Hong Di1,2 1Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Occult breast cancer (OBC) is a rare type of breast cancer that has not been well studied. The clinicopathological characteristics and treatment recommendations for OBC are based on a limited number of retrospective studies and thus remain controversial.Patients and methods: We identified 479 OBC patients and 115,739 non-OBC patients from 2004 to 2014 in and the Surveillance, Epidemiology, and End Results (SEER) database. The clinicopathological characteristics and survival outcomes were compared between OBC and non-OBC patients. We used the propensity score 1:1 matching analysis to evaluate OBC vs non-OBC comparison using balanced groups with respect to the observed covariates. We further divided the OBC population into four groups based on different treatment strategies. Univariable and multivariable analyses were used to calculate and compare the four treatment outcomes within the OBC population.Results: OBC patients were older, exhibited a more advanced stage, a higher rate of negative estrogen receptor and progesterone receptor status, a higher rate of HER2-positive status, and a higher rate of ≥10 positive lymph nodes, and were less likely to undergo surgical treatment than non-OBC patients. After adjustments for clinicopathological factors, the OBC patients exhibited a significantly better survival than the non-OBC patients (P

Zong-Chao Gou,1,2,* Xi-Yu Liu,1,2,* Yi Xiao,1,2 Shen Zhao,1,2 Yi-Zhou Jiang,1,2 Zhi-Ming Shao1–3 1Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Institutes of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Carcinoma of the axillary tail of Spence (CATS) is a poorly studied type of breast cancer. The clinicopathological characteristics and prognostic features of CATS are unclear. Methods: Using the Surveillance, Epidemiology, and End Results database, we identified 149,026 patients diagnosed with upper outer quadrant breast cancer (UOBC) (n=146,343) or CATS (n=2,683). The median follow-up was 88 months. The primary and secondary outcomes were breast cancer-specific survival (BCSS) and overall survival. The survival outcomes of UOBC and CATS were compared using competing risks analysis, log-rank test, Cox proportional hazards regression model, and propensity score matching method. Multivariate logistic regression was utilized to present the relationship between CATS and lymph node (LN) metastasis. Results: CATS presented a higher grade, higher negative hormone receptor rate, and more positive nodal metastasis. The 10-year BCSS rate was worse for CATS than for UOBC (85.1% vs 87.3%, P=0.001). The multivariate Cox analysis showed a higher hazard ratio (HR) for CATS over UOBC (BCSS: HR =1.20, P=0.001; overall survival: HR =1.11, P=0.019). The difference in the BCSS was also observed in a 1:1 matched cohort (BCSS P=0.019). A subgroup analysis revealed the inferior outcomes of CATS in the metastatic LN subgroup and the hormone receptor-negative subgroup. The multivariate logistic regression indicated that CATS is an independent contributing factor to LN metastasis. Conclusion: CATS had distinct clinicopathological characteristics and was more likely associated with LN metastasis. Compared to UOBC, CATS had adverse impacts on BCSS. Keywords: carcinoma of the axillary tail of Spence, upper outer quadrant breast cancer, breast cancer-specific survival, lymph node metastasis

To investigate the epidemiology, demographics and survival of mucinous adenocarcinomas (MACs), we identified 80,758 MAC patients in the Surveillance, Epidemiology and End Results (SEER) database. The reported incidence of MACs ebbed and flowed over time; however, a significant increase in reported annual age-adjusted incidences of MACs in the appendix, lung and bronchus was observed from 1981 to 2014. The demographics and outcomes of MACs differed by anatomic sites. MACs of the stomach had the largest percentage of poorly differentiated or undifferentiated tumors (41.2%), while MACs of the appendix and pancreas were associated with more advanced tumor stage (P

BackgroundTriple-negative breast cancers (TNBCs), especially those non-immune-inflamed tumors, have a poor prognosis and limited therapies. Human leukocyte antigen (HLA)-I not only contributes to antitumor immune response and the phenotype of the tumor microenvironment, but also is a negative predictor of outcomes after immunotherapy. However, the importance of HLA functional status in TNBCs remains poorly understood.MethodsUsing the largest original multiomics datasets on TNBCs, we systematically characterized the HLA-Ⅰ status of TNBCs from the perspective of HLA-Ⅰ homogeneity and loss of heterozygosity (LOH). The prognostic significance of HLA-I status was measured. To explain the potential mechanism of prognostic value in HLA-Ⅰ status, the mutational signature, copy number alteration, neoantigen and intratumoral heterogeneity were measured. Furthermore, the correlation between HLA-Ⅰ functional status and the tumor immune microenvironment was analyzed.ResultsLOH and homogeneity in HLA-I accounted for 18% and 21% of TNBCs, respectively. HLA-I LOH instead of HLA-I homogeneity was an independent prognostic biomarker in TNBCs. In particular, for patients with non-immune-inflamed tumors, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH. Furthermore, integrated genomic and transcriptomic analysis showed that HLA-I LOH was accompanied by upregulated scores of mutational signature 3 and homologous recombination deficiency scores, which implied the failure of DNA double-strand break repair. Moreover, HLA-I LOH had higher mutation and neoantigen loads and more subclones than HLA-I non-LOH. These results indicated that although HLA-I LOH tumors with failure of DNA double-strand break repair were prone to produce neoantigens, their limited capacity for antigen presentation finally contributed to poor immune selection pressure.ConclusionOur study illustrates the genomic landscape of HLA-I functional status and stresses the prognostic significance of HLA-I LOH in TNBCs. For “cold” tumors in TNBCs, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH.

Breast cancer is the most frequently diagnosed cancer in Chinese women, and early-stage patients are significantly increasing. Surgery is the main treatment for early-stage breast cancer with the “minimally invasive procedures” concept. The modality of breast cancer surgery has changed greatly in recent years in China, especially in our cancer center, Fudan University Shanghai Cancer Center (FUSCC). Firstly, pre-surgery biopsy is a routine procedure, which is mainly assisted by imaging instruments. Secondly, the number of breast-conserving surgery (BCS) and simple mastectomy procedures with or without sentinel lymph node biopsy (SM ± SLNB) is increasing gradually; radical mastectomy (RM) and modified radical mastectomy (MRM) are decreasing annually. Thirdly, SLNB has become a routine procedure in our center; it is safe and effective for replacing axillary lymph node dissection (ALND). Finally, reconstruction surgery has progressively advanced, although the operation cases are limited. This review article looks back at the development of breast cancer surgery, highlights the hallmarks of surgical management in our center as well as in China and discusses the future necessary efforts to improve the outcome and life quality for Chinese patients.

Tumor-initiating cells (TICs), or cancer stem cells (CSC), possess stem cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells (MaSCs) and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER− breast tumors, functionally promotes tumor initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signaling.

// Min He 1, * , Jia-Xin Zhang 1, * , Yi-Zhou Jiang 1 , Ying-Le Chen 1 , Hai-Yuan Yang 1 , Li-Chen Tang 1 , Zhi-Ming Shao 1 and Gen-Hong Di 1 1 Department of Breast Surgery, Key Laboratory of Breast Cancer, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China * These authors have contributed equally to this work Correspondence to: Gen-Hong Di, email: genhongdi@163.com Keywords: lymph node ratio, triple-negative breast cancer, prognosis Received: December 21, 2016 Accepted: March 29, 2017 Published: April 25, 2017 ABSTRACT Background: We aimed to evaluate the prognostic value of the lymph node ratio (LNR) in patients with axillary lymph node-positive triple-negative breast cancer (TNBC). Methods: The prognostic efficacy was investigated in the first cohort from the Surveillance, Epidemiology, and End Results (SEER) dataset (n=4114) and was further validated in an independent cohort from Fudan University Shanghai Cancer Center (n=417). Patients were classified into low-, medium- and high-risk LNR groups. Results: Multivariate analysis revealed that the LNR was an independent predictor of overall survival (hazard ratio (HR) for high-risk LNR: 3.24; 95% confidence interval (CI): 2.56 to 4.09) and breast cancer-specific survival (HR for high-risk LNR: 3.57; 95% CI: 2.76 to 4.62) in the SEER population and also for disease-free survival (HR for high-risk LNR: 4.29; 95% CI: 2.24-8.21) in the validation population. Subgroup analysis revealed that patient classification according to the LNR could discriminate among groups of patients with different survival rates based on pathological nodal (pN) staging. Conclusion: The LNR shows potential for use as an additional prognostic factor for TNBC patients with positive lymph node involvement. Considering the heterogeneity of TNBC, use of the LNR might allow for optimization of the pN staging system and should be considered when making treatment decisions.

Rationale: Paclitaxel resistance is a major concern when treating triple-negative breast cancer (TNBC) patients. We aimed to identify candidates causing paclitaxel resistance and explore their significance in TNBC therapeutics. Methods: A genome-wide CRISPR screening, integrated with transcriptome analyses, was performed to identify candidates involved in paclitaxel-resistant TNBCs. Cell proliferation, cytotoxicity, immunofluorescent staining, and xenograft assays were conducted to verify the phenotypes of paclitaxel resistance induced by candidate genes, both in vitro and in vivo. RNA sequencing, Western blotting, and chromatin immunoprecipitation assays were used to explore the underlying mechanisms. Results: MEF2-interacting transcriptional repressor (MITR), the truncated isoform of histone deacetylase 9 (HDAC9) lacking the deacetylation domain, was enriched in paclitaxel-resistant cells. Elevated MITR expression resulted in increased interleukin-11 (IL11) expression and activation of downstream JAK/STAT3 signaling. Mechanistically, MITR counteracted MEF2A-induced transcriptional suppression of IL11, ultimately causing paclitaxel resistance. By contrast, pharmacological inhibition of JAK1/2 by ruxolitinib reversed paclitaxel resistance both in vitro and in vivo. Conclusion: Our in vitro and in vivo genetic and cellular analyses elucidated the pivotal role of MITR/MEF2A/IL11 axis in paclitaxel resistance and provided a novel therapeutic strategy for TNBC patients to overcome poor chemotherapy responses.

Objective To evaluate the significance of postmastectomy radiotherapy (PMRT) in female breast cancer patients with T1-2N1M0 disease according to molecular subtypes and other risk factors. Method We conducted a retrospective cohort-based study utilizing the Surveillance, Epidemiology, and End Results database. Patients who were diagnosed with T1-2N1M0 invasive breast cancer and received mastectomy between 2010 and 2014 were enrolled in our study. Overall survival (OS) was calculated with Kaplan-Meier method, and multivariant Cox hazard model was conducted to identify the impact of PMRT according to molecular subtypes and other risk factors. Propensity score matching (PSM) was applied to balance measurable confounders. Results Of all the 16,521 enrolled patients, 5775 (35.0%) cases received PMRT. The distribution of molecular subtype is 71.4% for Luminal A, 13.2% for Luminal B, 5.1% for HER2 enriched, and 10.3% for TNBC. The OS was significantly better for patients in PMRT group than the Non-PMRT group (P, Highlights • T1-2N1 breast cancer is a heterogenous disease with different PMRT gain. • Survival benefit of PMRT varies among different clinicopathological risks. • PMRT improves OS in Luminal A patients with T1-2N1 breast cancer.

In article https://doi.org/10.1002/advs.201901728, Suling Liu and co‐workers report that the “decoy receptor” IL‐1 receptor 2 (IL1R2) is highly expressed on the most tumorigenic intermediate‐state breast tumor initiation cells (BTICs), which fall in between the epithelial‐like state and mesenchymal‐like state. IL‐1β in the tumor microenvironment activates the IL1R2 signaling pathway and then increases intermediate‐state BTIC self‐renewal and tumor progression, which can be specifically blocked by IL1R2 neutralizing antibody.

Breast tumor initiating cells (BTICs) with ALDH+CD24−CD44+ phenotype are the most tumorigenic and invasive cell population in breast cancer. However, the molecular mechanisms are still unclear. Here, it is found that a negative immune regulator interleukin‐1 receptor type 2 (IL1R2) is upregulated in breast cancer (BC) tissues and especially in BTICs. BC patients with high IL1R2 expression have a poorer overall survival and relapse‐free survival. High IL1R2 promotes BTIC self‐renewal and BC cell proliferation and invasion. Mechanistically, IL1R2 is activated by IL1β, as demonstrated by the fact that IL1β induces the release of IL1R2 intracellular domain (icd‐IL1R2) and icd‐IL1R2 then interacts with the deubiquitinase USP15 at the UBL2 domain and promotes its activity, which finally induces BMI1 deubiquitination at lysine 81 and stabilizes BMI1 protein. In addition, IL1R2 neutralizing antibody can suppress the protein expression of both IL1R2 and BMI1, and significantly abrogates the promoting effect of IL1R2 on BTIC self‐renewal and BC cell growth both in vitro and in vivo. The current results indicate that blocking IL1R2 with neutralizing antibody provides a therapeutic approach to inhibit BC progression by targeting BTICs., Interleukin‐1 receptor type 2 (IL1R2) increases BMI1 deubiquitination and stability via binding and enhancing the activity of ubiquitin‐specific protease 15 (USP15) in cell nuclei, intrinsically promoting the self‐renewal of breast tumor initiating cells (BTICs) as well as breast cancer cell proliferation and invasion. Targeting IL1R2 with its neutralizing antibody inhibits the self‐renewal of BTICs, breast tumorigenesis, and cancer resistance to docetaxel.

Background Age at the time of breast cancer diagnosis not only predicts clinical outcome but also indicates distinct molecular characteristics that provide the rationale for appropriate treatment strategies. However, to the authors' knowledge, little is known regarding the molecular profile and biological basis of triple-negative breast cancers (TNBCs) occurring in young and elderly patients. Methods Using the study institution's largest, single-center, multiomics TNBC data set, the authors analyzed the clinical and genomic features of young (aged ≤39 years) and elderly (aged ≥65 years) patients with TNBC. Results In the current study, a total of 50 patients, 354 patients, and 69 patients, respectively, were grouped as young, intermediate, and elderly patients with TNBC. Young patients with TNBC had worse short-term survival, upregulation of DNA repair, cell cycle and RNA metabolism gene sets, frequent pathogenic germline variants, and predominant homologous recombination deficiency-related mutational signatures. Several copy number alterations also were found to be enriched in young patients with TNBC. Nearly one-half of the TNBC cases in elderly patients were of the luminal androgen receptor subtype. TNBC in elderly patients was identified as being associated with severe fibrosis; a lower Ki-67 index; and somatic mutations in PIK3CA, KMT2D, ERBB2, ERBB3, and their corresponding pathways. Elderly patients with TNBC also were more likely to harbor targetable mutations. Conclusions The findings of the current study indicated that young patients with TNBC had an enhanced cell cycle, which may have helped to explain their inferior short-term survival, whereas the homologous recombination deficiency and enriched pathogenic germline variants observed among young patients with TNBC suggested the need for genetic counseling and testing, as well as the potential use of DNA damage agents and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. Molecular characteristics of elderly patients with TNBC, although suggesting less response to chemotherapy, provided a rationale for the routine detection of actionable somatic mutations.

Purpose: The tumor microenvironment has a profound impact on prognosis and immunotherapy. However, the landscape of the triple-negative breast cancer (TNBC) microenvironment has not been fully understood. Experimental Design: Using the largest original multi-omics dataset of TNBC (n = 386), we conducted an extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the TNBC microenvironment. We further analyzed the potential immune escape mechanisms of TNBC. Results: The TNBC microenvironment phenotypes were classified into three heterogeneous clusters: cluster 1, the “immune-desert” cluster, with low microenvironment cell infiltration; cluster 2, the “innate immune-inactivated” cluster, with resting innate immune cells and nonimmune stromal cells infiltration; and cluster 3, the “immune-inflamed” cluster, with abundant adaptive and innate immune cells infiltration. The clustering result was validated internally with pathologic sections and externally with The Cancer Genome Atlas and METABRIC cohorts. The microenvironment clusters had significant prognostic efficacy. In terms of potential immune escape mechanisms, cluster 1 was characterized by an incapability to attract immune cells, and MYC amplification was correlated with low immune infiltration. In cluster 2, chemotaxis but inactivation of innate immunity and low tumor antigen burden might contribute to immune escape, and mutations in the PI3K-AKT pathway might be correlated with this effect. Cluster 3 featured high expression of immune checkpoint molecules. Conclusions: Our study represents a step toward personalized immunotherapy for patients with TNBC. Immune checkpoint inhibitors might be effective for “immune-inflamed” cluster, and the transformation of “cold tumors” into “hot tumors” should be considered for “immune-desert” and “innate immune-inactivated” clusters.

The research area of the wearable electrochemical sensors is increasingly growing which are valuable for healthcare and fitness applications owing to their simplicity of operation, low-cost, and compact size. In this work, optimizing of programmable analog front-end for fully integrated wearable sweat sensor is proposed. The proposed system can detect glucose, lactate, sodium, potassium at the same time with low-power consumption which is suitable for continuous real-time sweat sensing system. The average power consumption of analog front-end in the proposed system is less than 2 mW at 3.3 V supply voltage.

Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model, we show that endocrine resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Consistently, similar gene expression changes are found in clinical breast tumours and patient-derived xenograft samples that are resistant to endocrine therapies. Mechanistically, the differential interactions between oestrogen receptor α and other oncogenic transcription factors, exemplified by GATA3 and AP1, drive global enhancer gain/loss reprogramming, profoundly altering breast cancer transcriptional programs. Our functional studies in multiple culture and xenograft models reveal a coordinated role of GATA3 and AP1 in re-organizing enhancer landscapes and regulating cancer phenotypes. Collectively, our study suggests that differential high-order assemblies of transcription factors on enhancers trigger genome-wide enhancer reprogramming, resulting in transcriptional transitions that promote tumour phenotypic plasticity and therapy resistance.