ACSL3 regulates breast cancer progression via lipid metabolism reprogramming and the YES1/YAP axis.

OBJECTIVE: Mitochondrial fatty acid oxidation is a metabolic pathway whose dysregulation is recognized as a critical factor in various cancers, because it sustains cancer cell survival, proliferation, and metastasis. The acyl-CoA synthetase long-chain (ACSL) family is known to activate long-chain fatty acids, yet the specific role of ACSL3 in breast cancer has not been determined. METHODS: We assessed the prognostic value of ACSL3 in breast cancer by using data from tumor samples. Gain-of-function and loss-of-function assays were also conducted to determine the roles and downstream regulatory mechanisms of ACSL3 in vitro and in vivo. RESULTS: ACSL3 expression was notably downregulated in breast cancer tissues compared with normal tissues, and this phenotype correlated with improved survival outcomes. Functional experiments revealed that ACSL3 knockdown in breast cancer cells promoted cell proliferation, migration, and epithelial-mesenchymal transition. Mechanistically, ACSL3 was found to inhibit ß-oxidation and the formation of associated byproducts, thereby suppressing malignant behavior in breast cancer. Importantly, ACSL3 was found to interact with YES proto-oncogene 1, a member of the Src family of tyrosine kinases, and to suppress its activation through phosphorylation at Tyr419. The decrease in activated YES1 consequently inhibited YAP1 nuclear colocalization and transcriptional complex formation, and the expression of its downstream genes in breast cancer cell nuclei. CONCLUSIONS: ACSL3 suppresses breast cancer progression by impeding lipid metabolism reprogramming, and inhibiting malignant behaviors through phospho-YES1 mediated inhibition of YAP1 and its downstream pathways. These findings suggest that ACSL3 may serve as a potential biomarker and target for comprehensive therapeutic strategies for breast cancer.

PROS1, a clinical prognostic biomarker and tumor suppressor, is associated with immune cell infiltration in breast cancer: A bioinformatics analysis combined with experimental verification.

BACKGROUND: PROS1 is an encoding gene that can generate protein S. This protein is a glycoprotein found in plasma that conducts physiological functions with vitamin K. However, the impact of its expression remains absent in the progression and prognosis of breast cancer (BC). METHODS: In this study, we comprehensively explored the expression of PROS1 in BC and its relationship with BC patient survival, prognosis, and other clinicopathological features. We investigated how PROS1 influenced the malignant biological behavior of BC cells. A series of enrichment analyses were conducted, and the immune landscape was explored in BC affected by PROS1. We also determined correlations between PROS1 and common drug sensitivities used for BC treatments. RESULTS: PROS1 had low expression in BC, which tended to result in poor survival of BC patients. Overexpressed PROS1 inhibited the migration and invasion of BC cells as well as the epithelial-mesenchymal transition process by downregulating SNAIL. Functional enrichment analyses revealed that PROS1 was more active in extracellular matrix (ECM) organization and structural constituent, ECM-receptor interaction, and other pathways with its related genes. PROS1 was also found to affect immune activity, including various immune cells infiltrating BC. BC patients with high PROS1 expression tended to have lower IC50 values of three common medications and obtained better efficacy. CONCLUSIONS: PROS1 can become a promising prognostic factor and a possible therapeutic target in BC patients and suppress BC cell metastatic potential. In addition, PROS1 is a crucial factor in immune infiltration in BC.

KLHL29-mediated DDX3X degradation promotes chemosensitivity by abrogating cell cycle checkpoint in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype and accounts for approximately 15-20% of breast cancer cases. In this study, we identified KLHL29, which is an understudied member of the Kelch-like gene family, as a crucial tumor suppressor that regulates chemosensitivity in TNBC. KLHL29 expression was significantly downregulated in breast cancer tissues compared with adjacent normal tissues, and low levels of KLHL29 were associated with unfavorable prognoses. Ectopic KLHL29 suppressed, while depleting KLHL29 promoted, the growth, proliferation, migration, and invasion of TNBC. Mechanistically, KLHL29 recruited the CUL3 E3-ligase to the RNA-binding protein DDX3X, leading to the proteasomal degradation of the latter. This downregulation of DDX3X resulted in the destabilization of CCND1 mRNA and the consequent cell cycle arrest at G0/G1 phase. Remarkably, the DDX3X inhibitor RK33 combined with platinum-based chemotherapy can synergistically suppress TNBC that usually expresses low levels of KLHL29 and high levels of DDX3X using cancer cell-derived xenograft and patient-derived organoids models. Altogether, we uncovered the potential role for the KLHL29-DDX3X signaling cascade in the regulation of TNBC progression, thus providing a promising combination strategy for overcoming TNBC chemoresistance.

ARHGAP39 is a prognostic biomarker involved in immune infiltration in breast cancer.

BACKGROUND: Current studies on the role of ARHGAP39 mainly focused on its effect on neurodevelopment. However, there are few studies on the comprehensive analysis of ARHGAP39 in breast cancer. METHODS: ARHGAP39 expression level was analyzed based on the Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression Project (GTEx), and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database and validated by qPCR in various cell lines and tumor tissues. The prognostic value was analyzed using Kaplan-Meier curve analysis. CCK-8 and transwell assays were conducted to identify the biological function of ARHGAP39 in tumorigenesis. Signaling pathways related to ARHGAP39 expression were identified by the GO and KEGG enrichment analysis and gene set enrichment analysis (GSEA). The correlations between ARHGAP39 and cancer immune infiltrates were investigated via TIMER, CIBERSORT, ESTIMATE and tumor-immune system interactions database (TISIDB). RESULTS: ARHGAP39 was overexpressed in breast cancer and associated with poor survival outcomes. In vitro experiments revealed that ARHGAP39 could facilitate the proliferation, migration, and invasion capability of breast cancer cells. GSEA analysis showed that the main enrichment pathways of ARHGAP39 was immunity-related pathways. Considering the immune infiltration level, ARHGAP39 was negatively associated with infiltrating levels of CD8 + T cell and macrophage, and positively associated with CD4 + T cell. Furthermore, ARHGAP39 was significantly negatively correlated with immune score, stromal score, and ESTIMATE score. CONCLUSIONS: Our findings suggested that ARHGAP39 can be used as a potential therapeutic target and prognostic biomarker in breast cancer. ARHGAP39 was indeed a determinant factor of immune infiltration.

Predicting Pathological Complete Response in Breast Cancer After Two Cycles of Neoadjuvant Chemotherapy by Tumor Reduction Rate: A Retrospective Case-Control Study.

PURPOSE: We aimed to identify effectiveness-associated indicators and evaluate the optimal tumor reduction rate (TRR) after two cycles of neoadjuvant chemotherapy (NAC) in patients with invasive breast cancer. METHODS: This retrospective case-control study included patients who underwent at least four cycles of NAC at the Department of Breast Surgery between February 2013 and February 2020. A regression nomogram model for predicting pathological responses was constructed based on potential indicators. RESULTS: A total of 784 patients were included, of whom 170 (21.68%) reported pathological complete response (pCR) after NAC and 614 (78.32%) had residual invasive tumors. The clinical T stage, clinical N stage, molecular subtype, and TRR were identified as independent predictors of pCR. Patients with a TRR > 35% were more likely to achieve pCR (odds ratio, 5.396; 95% confidence interval [CI], 3.299-8.825). The receiver operating characteristic (ROC) curve was plotted using the probability value, and the area under the ROC curve was 0.892 (95% CI, 0.863-0.922). CONCLUSION: TRR > 35% is predictive of pCR after two cycles of NAC, and an early evaluation model using a nomogram based on five indicators, age, clinical T stage, clinical N stage, molecular subtype, and TRR, is applicable in patients with invasive breast cancer.

UTP11 deficiency suppresses cancer development via nucleolar stress and ferroptosis.

The eukaryotic ribosome is essential for cancer cell survival. Perturbation of ribosome biogenesis induces nucleolar stress or ribosomal stress, which restrains cancer growth, as rapidly proliferating cancer cells need more active ribosome biogenesis. In this study, we found that UTP11 plays an important role in the biosynthesis of 18S ribosomal RNAs (rRNA) by binding to the pre-rRNA processing factor, MPP10. UTP11 is overexpressed in human cancers and associated with poor prognoses. Interestingly, depletion of UTP11 inhibits cancer cell growth in vitro and in vivo through p53-depedednt and -independent mechanisms, whereas UTP11 overexpression promotes cancer cell growth and progression. On the one hand, the ablation of UTP11 impedes 18S rRNA biosynthesis to trigger nucleolar stress, thereby preventing MDM2-mediated p53 ubiquitination and degradation through ribosomal proteins, RPL5 and RPL11. On the other hand, UTP11 deficiency represses the expression of SLC7A11 by promoting the decay of NRF2 mRNA, resulting in reduced levels of glutathione (GSH) and enhanced ferroptosis. Altogether, our study uncovers a critical role for UTP11 in maintaining cancer cell survival and growth, as depleting UTP11 leads to p53-dependent cancer cell growth arrest and p53-independent ferroptosis.

Recent Insights into the Role of Gut Microbiota in Diabetic Retinopathy.

The microbiome has become a hot issue in recent years. The composition, modification, alteration, and disturbance of gut microbiota were found to influence important physiological processes, including energy metabolism and microenvironmental homeostasis, and lead to various diseases, including obesity, type 2 diabetes mellitus and chronic kidney disease. Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus and one of the leading causes of blindness and vision impairment. The underlying mechanisms in DR pathogenesis remain limited. Recently, important insights have been made regarding possible connections between gut microbiome dysbiosis and ocular disease including DR, uveitis, glaucoma, and age-related macular degeneration, and the concept of a "microbiota-gut-retina axis" has been put forward. Hence, we reviewed current understanding of the relationship between DR and gut microbiota. We summarized potential pathophysiological mechanisms that contribute to the role of the gut microbiota on DR, including hyperglycemia, anti-diabetes drugs, microbial metabolites, and inflammatory properties. We aimed to find novel effective therapeutic options to prevent the onset and development of DR.

The choice of a neoadjuvant chemotherapy cycle for breast cancer has significance in clinical practice: results from a population-based, real world study.

OBJECTIVE: Neoadjuvant chemotherapy (NAC) is currently used in both early stage and locally advanced breast cancers. The survival benefits of standard vs. non-standard NAC cycles are still unclear. This study aimed to investigate the relationship between NAC cycles and survival based on real world data. METHODS: We identified patients diagnosed with invasive primary breast cancers who underwent NAC followed by surgery. Patients who received at least 4 NAC cycles were defined as having received standard cycles, while patients who received less than 4 NAC cycles were defined as having received non-standard cycles. Kaplan-Meier curves and Cox proportional hazard models were used to estimate the disease-free survival (DFS) and overall survival (OS). RESULTS: Of the 1,024 included patients, 700 patients received standard NAC cycles and 324 patients received non-standard NAC cycles. The DFS estimates were 87.1% and 81.0% (P = 0.007) and the OS estimates were 90.0% and 82.6% (P = 0.001) in the standard and non-standard groups, respectively. Using multivariate analyses, patients treated with standard NAC cycles showed significant survival benefits in both DFS [hazard ratio (HR): 0.62, 95% confidence interval (CI): 0.44-0.88] and OS (HR: 0.54, 95% CI: 0.37-0.79). Using stratified analyses, standard NAC cycles were associated with improved DFS (HR: 0.59, 95% CI: 0.36-0.96) and OS (HR: 0.49, 95% CI: 0.28-0.86) in the HER2 positive group. Similar DFS (HR: 0.50, 95% CI: 0.25-0.98) and OS (HR: 0.45, 95% CI: 0.22-0.91) benefits were shown for the triple negative group. CONCLUSIONS: Standard NAC cycles were associated with a significant survival benefit, especially in patients with HER2 positive or triple negative breast cancer.

HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia.

Background: Hypoxia is a hallmark of the physical microenvironment of solid tumors. As a key factor that regulates tumor development and progression, hypoxia can reprogram the expression of multiple genes, whose biological function and molecular mechanism in cancer remain largely unclear. The mitochondrial ribosome protein family consists of nuclear-encoded mitochondrial proteins that are responsible for protein synthesis in the mitochondria. Methods: A high-throughput RNA sequencing assay was carried out to identify differentially expressed mRNAs between breast cancer tissues and adjacent normal tissues as well as breast tumors with metastasis and those without metastasis. Our clinical samples and TCGA database were analyzed to observe the clinical value of mitochondrial ribosome protein L52 (MRPL52) in human breast cancer. Potent hypoxia response elements in the promoter region of MRPL52 were identified and validated by chromatin immunoprecipitation and luciferase reporter assays. Functional experiments were performed using breast cancer cell lines with MRPL52 ectopic expression and knockdown cultured in a 20% or 1% O2 environment. Results: MRPL52 expression was upregulated in human breast cancer and was significantly associated with aggressive clinicopathological characteristics and a higher metastatic risk of breast cancer patients. We found that the overexpression of MRPL52 in breast cancer is induced by hypoxia-inducible factor-1 in response to hypoxic exposure. The role of MRPL52 in suppressing apoptosis and promoting migration and invasion of hypoxic breast cancer cells was demonstrated by our experimental evidence. Mechanistically, MRPL52 promoted PTEN-induced putative kinase 1 /Parkin-dependent mitophagy to remove oxidatively damaged mitochondria and prevent uncontrolled reactive oxygen species (ROS) generation, thus repressing activation of the mitochondrial apoptotic cascade. Additionally, MRPL52 augmented epithelial-mesenchymal transition, migration and invasion of hypoxic breast cancer cells by activating the ROS-Notch1-Snail signaling pathway. Benefited from this bidirectional regulatory mechanism, MRPL52 is responsible for maintaining ROS levels in a window that can induce tumorigenic signal transduction without causing cytotoxicity in hypoxic breast cancer cells. Conclusions: This work elucidates the molecular mechanism by which MRPL52 mediates hypoxia-induced apoptotic resistance and metastatic initiation of breast cancer, and provides new insights into the interplay between cancer and the tumor microenvironment.

An Immune Model to Predict Prognosis of Breast Cancer Patients Receiving Neoadjuvant Chemotherapy Based on Support Vector Machine.

Tumor microenvironment has been increasingly proved to be crucial during the development of breast cancer. The theory about the conversion of cold and hot tumor attracted the attention to the influences of traditional therapeutic strategies on immune system. Various genetic models have been constructed, although the relation between immune system and local microenvironment still remains unclear. In this study, we tested and collected the immune index of 262 breast cancer patients before and after neoadjuvant chemotherapy. Five indexes were selected and analyzed to form the prediction model, including the ratio values between after and before neoadjuvant chemotherapy of CD4+/CD8+ T cell ratio; lymphosum of T, B, and natural killer (NK) cells; CD3+CD8+ cytotoxic T cell percent; CD16+CD56+ NK cell absolute value; and CD3+CD4+ helper T cell percent. Interestingly, these characters are both the ratio value of immune status after neoadjuvant chemotherapy to the baseline. Then the prediction model was constructed by support vector machine (accuracy rate = 75.71%, area under curve = 0.793). Beyond the prognostic effect and prediction significance, the study instead emphasized the importance of immune status in traditional systemic therapies. The result provided new evidence that the dynamic change of immune status during neoadjuvant chemotherapy should be paid more attention.

The Triglyceride-Glucose Index is Associated with Diabetic Retinopathy in Chinese Patients with Type 2 Diabetes: A Hospital-Based, Nested, Case-Control Study.

BACKGROUND: This study aimed to investigate the association between the triglyceride-glucose (TyG) index and diabetic retinopathy (DR) in Chinese patients with type 2 diabetes. METHODS: In this nested case-control study, all diabetic participants were registered hospitalizations during 2012-2018, including 596 with DR as cases and three matching controls per case. DR was assessed using Early Treatment Diabetic Retinopathy Study criteria. The TyG index was calculated: Ln (fasting blood glucose [mg/dL] × fasting triglycerides [mg/dL] ÷ 2). Multivariate logistic regression, a receiver-operating characteristic (ROC) curve, linear regression models, and mediation analysis were used to explore associations. RESULTS: The TyG index was lower in DR and decreased as its severity advanced among 2,112 subjects (P=0.005). After confounders (sex, duration of diabetes, use of antidiabetic agents, heart rate, systolic blood pressure, pulse pressure, height, weight, body-mass index, and glycated hemoglobin) had been accounted for, there were significant associations between the TyG index and any-severity DR (OR 0.83, 95% CI 0.73-0.95; P=0.006), as well as vision-threatening DR (VTDR; OR 0.53, 95% CI 0.36-0.76; P=0.001). ROC analysis indicated that the TyG index showed significant discriminatory ability in any-severity DR (area under curve [AUC] 0.534, P=0.015) and VTDR (AUC 0.624, P=0.001). CONCLUSION: The TyG index was associated with the presence and severity of DR. Our findings suggest that the TyG index may become a useful biomarker in evaluating and following the presence of DR and VTDR.

TuYou-County Pediatric Eye (TYPE) study, design issues, baseline demographic characteristics, and implications: Report number 1.

ABSTRACT: To report the rationale, design, and baseline demographic characteristics of TuYou-County Pediatric Eye study, which mainly aimed to determine the retinal microvascular changes with optical coherence tomography angiography (OCTA) and its association with eye abnormalities in school aged children and adolescents at suburban location in Northern China.TuYou-County Pediatric Eye study was a school-based survey conducted in TuYou-County. Multi-ethnic (Mongol, Han, and Hui) participants will be followed up for 5 years. Standardized ophthalmological examinations include visual acuity, ocular biometry, retinal photography, and OCTA. A questionnaire survey was conducted to collect variables regarding to eye disease such as parental history of eye diseases, near work, outdoor activities, living and eating habits, etc.After sampling, 687 participants were eligible for investigation, and 20 students did not attend the investigation, living 667 (response rate, 97.1%) students completed questionnaires and all ocular examinations. The average age of all participants was 14.9 ±â€Š5.11.TYPE study is the first large-scale school-based multi-ethnic survey in suburban site of Northern China. Continuous identification of retinal microvascular changes with eye diseases will provide new insights into the control related diseases in school-age children and adolescents.

Updated Bayesian Network Meta-Analysis of Adjuvant Targeted Treatment Regimens for Early Human Epidermal Growth Factor Receptor-2 Positive Breast Cancer.

PURPOSE: Combining targeted agents with adjuvant chemotherapy prolongs survival in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, but also increases the risk of adverse effects. The updated results of 3 randomized controlled trials (RCTs) were reported in 2019. Given the lack of adequate head-to-head pairwise assessment for anti-HER2 agents, network meta-analysis facilitates obtaining more precise inference for evidence-based therapy. METHODS: RCTs comparing at least 2 anti-HER2 regimens in an adjuvant setting for HER2-positive early-stage breast cancer (EBC) were included. Hazard ratios for overall survival (OS) and disease free survival (DFS), with respective 95% confidence intervals were pooled for assessment of efficacy. A Bayesian statistical model was used, and odds ratios (ORs) for adverse events (AEs) were used to pool effect sizes. RESULTS: We demonstrated that 1-year trastuzumab plus chemotherapy had increased efficacy compared to shorter or longer treatment duration. The OR of cardiac events gradually increased from 6 months to 1 and 2-year trastuzumab arms, relative to chemotherapy only. Compared to trastuzumab plus chemotherapy, dual HER2-targeting therapies increased DFS, especially for hormone receptor negative patients. Dual anti-HER2 blockade regimens revealed an increased probability of gastrointestinal reactions. As a second agent, pertuzumab showed significantly higher DFS and OS. CONCLUSION: We conclude that 1-year adjuvant trastuzumab should remain as the standard treatment for HER2-positive EBC patients, as it has greater efficacy and a manageable proportion of AEs. Clinical efficacy can be increased for hormone receptor-negative tumors by including a second HER2-targeted agent to the treatment regimen. For hormone receptor-positive cases with basal disease, it is acceptable to reduce the risk of cardiotoxicity by shortening the duration of trastuzumab.

Role of Proton-Coupled Monocarboxylate Transporters in Cancer: From Metabolic Crosstalk to Therapeutic Potential.

Proton-coupled monocarboxylate transporters (MCTs), representing the first four isoforms of the SLC16A gene family, mainly participate in the transport of lactate, pyruvate, and other monocarboxylates. Cancer cells exhibit a metabolic shift from oxidative metabolism to an enhanced glycolytic phenotype, leading to a higher production of lactate in the cytoplasm. Excessive accumulation of lactate threatens the survival of cancer cells, and the overexpression of proton-coupled MCTs observed in multiple types of cancer facilitates enhanced export of lactate from highly glycolytic cancer cells. Proton-coupled MCTs not only play critical roles in the metabolic symbiosis between hypoxic and normoxic cancer cells within tumors but also mediate metabolic interaction between cancer cells and cancer-associated stromal cells. Of the four proton-coupled MCTs, MCT1 and MCT4 are the predominantly expressed isoforms in cancer and have been identified as potential therapeutic targets in cancer. Therefore, in this review, we primarily focus on the roles of MCT1 and MCT4 in the metabolic reprogramming of cancer cells under hypoxic and nutrient-deprived conditions. Additionally, we discuss how MCT1 and MCT4 serve as metabolic links between cancer cells and cancer-associated stromal cells via transport of crucial monocarboxylates, as well as present emerging opportunities and challenges in targeting MCT1 and MCT4 for cancer treatment.

Exploring the Metabolic Vulnerabilities of Epithelial-Mesenchymal Transition in Breast Cancer.

Metastasis and drug resistance are the leading causes of death for breast cancer patients. Epithelial-mesenchymal transition (EMT), a transition from polarized epithelial cells to motile mesenchymal cells mediated by a series of activation signals, confers breast tumor cells with enhanced stem cell, invasive, and metastatic properties. Metabolic reprogramming is an emerging hallmark of cancer cells, which have a complex mutual effect with EMT process. Under hypoxic and nutrient-deprived conditions, metabolic rewiring can rapidly provide ATP and sufficient metabolic intermediates for fueling breast cancer metastasis and progression. In this review, we primarily focus on how these altered metabolic phenotypes of breast tumor cells activate the EMT transcription factors and induce the EMT process to further promote metastasis and resistance to therapy. This review is divided to glucose, lipid, and amino acid metabolism to explore for potential metabolic vulnerabilities, which may provide new insights for blocking the EMT process in breast cancer.

Serum CA125 Level Is Associated with Diabetic Retinopathy in Chinese Patients with Type 2 Diabetes.

BACKGROUND: To investigate the association between serum carbohydrate antigen 125 (CA125) and the presence as well as severity of diabetes retinopathy (DR) in Chinese adult patients with type 2 diabetes. METHODS: A hospital-based cross-sectional study was conducted from February 2012 to November 2018. DR was assessed using Early Treatment Diabetic Retinopathy Study criteria. Vision-threatening DR (VTDR) was diagnosed if subjects had severe non-proliferative DR (NPDR), proliferative DR (PDR), or clinically significant macular edema (CSME). Multivariate logistic regression models were applied to explore the associations. RESULTS: Among the 2696 participants, the overall prevalence of DR was 25.1%, of which the prevalence of mild NPDR, moderate NPDR, and VTDR was 10.8%, 4.5%, and 9.9%, respectively. Serum CA125 level was significantly higher in participants with DR and increased with the severity of DR (P = 0.013). After accounting for age, gender, smoking, drinking, duration of diabetes, anti-diabetic agents use, systolic blood pressure, pulse pressure, weight, hemoglobin A1c and fasting plasma glucose levels, CA125 level was significantly associated with subjects in any-severity DR (odds ratio [OR] 1.006 [95% confidence interval CI: 1.002-1.010], P = 0.006) and VTDR (1.008 [1.003-1.013], P = 0.001). When CA125 was treated as categorized variables, the prevalence of VTDR might increase as improving CA125 quartiles (P value for trend = 0.017). CONCLUSION: In this study, serum CA125 level was associated with the presence and severity of DR in Chinese patients with type 2 diabetes. Further prospective studies should be warranted to validate the feasible role of CA125 as well as other biomarkers.

Metabolic Reprogramming in Triple-Negative Breast Cancer.

Metabolic reprogramming is an emerging hallmark of cancer cells, in which cancer cells exhibit distinct metabolic phenotypes to fuel their proliferation and progression. The significant advancements made in the area of metabolic reprogramming make possible new strategies for overcoming malignant cancer, including triple-negative breast cancer. Triple-negative breast cancer (TNBC) is associated with high histologic grade, aggressive phenotype, and poor prognosis. Even though triple-negative breast cancer patients benefit from standard chemotherapy, they still face high recurrence rates and are more likely to develop resistance to chemotherapeutic drugs. Therefore, there is an urgent need to explore vulnerabilities of triple-negative breast cancer and develop novel therapeutic drugs to improve clinical outcomes for triple-negative breast cancer patients. Metabolic reprogramming may provide promising therapeutic targets for the treatment of triple-negative breast cancer. In this paper, we primarily discuss how triple-negative breast cancer cells reprogram their metabolic phenotype and that of stromal cells in the microenvironment to survive under nutrient-poor conditions. Considering that metastasis and chemoresistance are the main contributors to mortality in triple-negative breast cancer patients, we also focus on the role of metabolic adaption in mediating metastasis and chemoresistance of triple-negative breast cancer tumors.

Can ACEI/ARB prevent the cardiotoxicity caused by chemotherapy in early-stage breast cancer?-a meta-analysis of randomized controlled trials.

BACKGROUND: Administration of anthracycline-based chemotherapy with or without trastuzumab is recognized as standard care for breast cancer, but it is associated with a decline in left ventricular ejection fraction (LVEF). Angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB) might decrease this cardiac dysfunction caused by the anti-cancer therapy. We sought to evaluate the prophylactic effects of the cardioprotective agents ACEI/ARB for early-stage breast cancer. METHODS: We systematically searched the electronic databases Cochrane, PubMed, and Embase for randomized controlled trials (RCTs) evaluating the effect of ACEI/ARB. This meta-analysis calculated weighted mean differences with 95% CI, for ejection fraction and pooled odds ratios (OR) with 95% CI, for cardiac events. Pooled analyses were used in a random-effect model. The primary endpoint was the change of LVEF in the ACEI/ARB group versus the control group from baseline through completion of the studies. RESULTS: our meta-analysis includes 5 studies encompassing 702 early-stage breast cancer patients. There was statistically significant diversity in the magnitude of the change of mean LVEF in patients receiving ACEI/ARB compared with control groups, with a mean difference of 4.08% (95% CI: 0.8% to 7.35%, P=0.01). However, regarding patient outcomes, ACEI/ARB did not significantly reduce the risk of cardiac events (OR 0.91, 95% CI: 0.62 to 1.34, P=0.64) or increase the incidence of hypotension events as compared with controls (OR 2.72, 95% CI: 0.69 to 10.73, P=0.15). CONCLUSIONS: Our study suggests that ACEI/ARB significantly attenuate the cardiac dysfunction caused by anthracycline-based chemotherapy and/or trastuzumab. Further studies are required to confirm the effectiveness of this cardioprotective agent.