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Breast cancer is one of the leading cancer deaths around the world. Targeted drugs have greatly increased the survival rate of breast cancer patients in recent years. But in some patients, the current regimen is still ineffective. Therefore, more therapeutic targets for treating breast cancer are demanding. The core heterochromatin-related genes of breast cancer were identified by utilizing prognostic survival analysis and multivariate Cox hazard proportional regression analysis. Both breast cancer and adjacent normal tissue were collected and analyzed with western blot and immunohistochemistry. Colony formation assay, CCK8 assay, and EdU assay were used to measure the effect of CBX3 on breast cancer cell growth, wound-healing assay and Transwell assay were used to analyze the effect of CBX3 on breast cancer cell migration and invasion. Flow cytometry assay and western blot were used to study the molecular mechanism of CBX3 in breast cancer. High expression of heterochromatin-related proteins CBX3, H2AFY, and SULF1 showed a poor prognosis in patients in both TCGA dataset and GEO datasets. Western blot demonstrated that the expression level of CBX3 was significantly higher in breast cancer than that in adjacent normal tissues. Colony formation assay, CCK8 assay, and EdU assay showed that the knockdown of CBX3 could significantly inhibit breast cancer cell growth, and the overexpression of CBX3 could promote the growth of breast cancer cells. Transwell assay and wound healing assay showed that knockdown of CBX3 inhibited breast cancer cell migration and invasion, and the overexpression of CBX3 promoted breast cancer cell migration and invasion. Western blot showed that CBX3 might promote breast cancer cell proliferation, invasion, and migration in breast cancer by modulating the ERK1/2 signaling pathway and epithelial-mesenchymal transition (EMT)-related genes. CBX3 was a biomarker of poor prognosis in breast cancer patients. CBX3 promoted the proliferation of breast cancer cells through the ERK signaling pathway, and migration and invasion of breast cancer cells through EMT-related genes. The CBX3/p-ERK1/2 signaling axis might provide a new therapeutic method against breast cancer.

Glucose metabolism disorder is a common feature in cancer. Cancer cells generate much energy through anaerobic glycolysis, which promote the development of tumors. However, long non-coding RNA may play an important role in this process. Our aim is to explore a prognostic risk model based on the glucose metabolism-related lncRNAs which provides clues that lncRNAs predict a clinical outcome through glucose metabolism in breast cancer.1222 RNA-seq were extracted from the TCGA database, and 74 glucose metabolism-related genes were loaded from the GSEA website. Then, 7 glucose metabolism-related lncRNAs risk score model was developed by univariate, Lasso, and multivariate regression analysis. The lncRNA risk model showed that high-risk patients predict a poor clinical outcome with high reliability (P=2.838×10-6). Univariate and multivariate independent prognostic analysis and ROC curve analysis proved that the risk score was an independent prognostic factor in breast cancer with an AUC value of 0.652. Finally, Gene set enrichment analysis showed that cell cycle-related pathways were significantly enriched in a high-risk group.Our results showed that glucose metabolism-related lncRNAs can affect breast cancer progression. 7 glucose metabolism-related lncRNAs prognostic signature was established to evaluate the OS of patients with breast cancer. PICSAR, LINC00839, AP001505.1, LINC00393 were risk factors and expressed highly in the high-risk group. A Nomogram was made based on this signature to judge patients' living conditions and prognosis.7 glucose metabolism-related lncRNAs risk score model had a high prognostic value in breast cancer. PICSAR, LINC00839, AP001505.1, LINC00393 were risk factors. AP001505.1 expression was increased in most triple-negative breast cancer cells treated with high glucose, which may also take part in breast cancer progression and potential therapeutic targets.

To explore the influence and the underlying mechanism of vaspin (visceral adipose tissue-derived serpin) on the development of triple-negative breast malignancy.First, we analyzed medical records and screened out 22 breast cancer patients with different BMI according to inclusion and exclusion criterion, and measured serum vaspin of those patients. Then we studied the effects of vaspin on TNBC cell lines by using EdU assay, colony formation, transwell and wound-healing assay. Later, we used bioinformatics analysis to identify downstream effectors and verify with qRT-PCR, luciferase assay, western blot, etc. RESULTS: We found the vaspin level was positively correlated with BMI in breast malignant patients and vaspin could significantly enhance the proliferation, infiltration and transferring of triple-negative breast cancer cells by restraining the expression of miR-33a-5p. By using bioinformatic analysis and luciferase assay, we identified miR-33a-5p directly regulating ABHD2.Vaspin, as a cancer-promoting cytokine, may inhibit miR-33a-5p thus increasing the level of ABHD2 to promote the development of the triple-negative breast cancer.

Purpose To investigate the mechanism underlying the modulation of M1 macrophage polarization by exosomes released from hyperthermia-treated triple-negative breast cancer (TNBC) cells. Materials and methods In this study, the effects of hyperthermia on TNBC cells were examined using cell counting kit-8, apoptosis, and cell cycle assays. Transmission electron microscopy was used to identify the structure of exosomes, while bicinchoninic acid and nanoparticle tracking analysis were used to detect particle size and amounts of exosomes released after hyperthermia. The polarization of macrophages incubated with exosomes derived by hyperthermia-pretreated TNBC cells were assessed by RT-qPCR and flow cytometry analysis. Next, RNA sequencing was performed to determine the targeting molecules changed in hyperthermia-treated TNBC cells in vitro. Finally, the mechanism underlying the modulation of macrophage polarization by exosomes derived from hyperthermia-treated TNBC cells was examined by using RT-qPCR, immunofluorescence and flow cytometry analysis. Results Hyperthermia markedly reduced cell viability in TNBC cells and promoted the secretion of TNBC cell-derived exosomes. The hub genes of hyperthermia-treated TNBC cells were significantly correlated with macrophage infiltration. Additionally, hyperthermia-treated TNBC cell-derived exosomes promoted M1 macrophage polarization. Furthermore, the expression levels of heat shock proteins, including HSPA1A, HSPA1B, HSPA6, and HSPB8, were significantly upregulated upon hyperthermia treatment, with HSPB8 exhibiting the highest upregulation. Moreover, hyperthermia can induce M1 macrophage polarization by promoting exosome-mediated HSPB8 transfer. Conclusion This study demonstrated a novel mechanism that hyperthermia can induce M1 polarization of macrophages via exosome-mediated HSPB8 transfer. These results will help with future development of an optimized hyperthermia treatment regime for clinical application, especially for combination treatment with immunotherapy.

Purpose To investigate the mechanism through which hyperthermia promotes exosome secretion and drug sensitivity in adriamycin-resistant breast cancer. Materials and Methods We first evaluated the effect of hyperthermia on adriamycin-resistant breast cancer viability and used transmission electron microscopy, nanoparticle tracking analysis, and a bicinchoninic acid kit to validate the effect of hyperthermia on exosome secretion. The effective targeting molecules and pathways changed by hyperthermia were explored by RNA microarray and verified in vitro. The adriamycin-resistant MCF-7/ADR cells co-incubated with the exosomes produced by MCF-7/ADR cells after hyperthermia were assessed. The uptake of exosomes by MCF-7/ADR cells after hyperthermia treatment was evaluated by confocal microscopy. Finally, the mechanism through which hyperthermia promotes exosome secretion by hyperthermia was determined. Results Hyperthermia significantly suppressed the growth of adriamycin-resistant breast cancer cells and increased drug sensitivity by upregulating FOS and CREB5, genes related to longer overall survival in breast cancer patients. Moreover, hyperthermia promoted exosome secretion through Rab7b, a small GTPase that controls endosome transport. The upregulated FOS and CREB5 antioncogenes can be transferred to MCF-7/ADR cells by hyperthermia-treated MCF-7/ADR cell-secreted exosomes. Conclusions Our results demonstrated a novel function of hyperthermia in promoting exosome secretion in adriamycin-resistant breast cancer cells and revealed the effects of hyperthermia on tumor cell biology. These hyperthermia-triggered exosomes can carry antitumor genes to the residual tumor and tumor microenvironment, which may be more beneficial to the effects of hyperthermia. These results represent an exploration of the relationship between therapeutic strategies and exosome biology.

Background: Tumor antigenicity and efficiency of antigen presentation jointly influence tumor immunogenicity, which largely determines the effectiveness of immune checkpoint blockade (ICB). However, the role of altered antigen processing and presentation machinery (APM) in breast cancer (BRCA) has not been fully elucidated. Methods: A series of bioinformatic analyses and machine learning strategies were performed to construct APM-related gene signatures to guide personalized treatment for BRCA patients. A single-sample gene set enrichment analysis (ssGSEA) algorithm and weighted gene co-expression network analysis (WGCNA) were combined to screen for BRCA-specific APM-related genes. The non-negative matrix factorization (NMF) algorithm was used to divide the cohort into different clusters and the fgsea algorithm was applied to investigate the altered signaling pathways. Random survival forest (RSF) and the least absolute shrinkage and selection operator (Lasso) Cox regression analysis were combined to construct an APM-related risk score (APMrs) signature to predict overall survival. Furthermore, a nomogram and decision tree were generated to improve predictive accuracy and risk stratification for individual patients. Based on Tumor Immune Dysfunction and Exclusion (TIDE) method, random forest (RF) and Lasso logistic regression model were combined to establish an APM-related immunotherapeutic response score (APMis). Finally, immune infiltration, immunomodulators, mutational patterns, and potentially applicable drugs were comprehensively analyzed in different APM-related risk groups. Results: In this study, APMrs and APMis showed favorable performances in risk stratification and therapeutic prediction for BRCA patients. APMrs exhibited more powerful prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. APMrs was closely associated with distinct mutational patterns, immune cell infiltration and immunomodulators expression. Furthermore, the two APM-related gene signatures were independently validated in external cohorts with prognosis or immunotherapeutic responses. Potential applicable drugs and targets were further mined in the APMrs-high group. Conclusion: The APM-related gene signatures established in our study could improve the personalized assessment of survival risk and guide ICB decision-making for BRCA patients.

IntroductionWhile most epidemiological studies have focused on the effects of individual dietary patterns and nutritional status on health, the relationships between the combinations of these factors and patient prognosis requires further investigation.ObjectiveThis study explored mortality risk in individuals with different combinations of dietary patterns or nutritional status.MethodsUnsupervised K-means clustering was used to classify populations. The analyses included Cox proportional risk and competing risk models.ResultsAfter considering a complex sampling design, the results showed that among 12,724 participants aged >60 years, 6.99% died from cancer and 10.47% from cardiovascular and cerebrovascular disease (CCVD). After correcting for participant baseline information and chronic conditions, the geriatric nutritional risk index and healthy eating index (HEI) were negatively associated with the risk of all-cause and cause-specific mortality. The opposite was true for the dietary inflammatory index (DII). After sorting the population three clusters based on study scores showed higher risks of all-cause mortality and cancer-related death in Cluster 2 and 3.DiscussionThese results suggest that different nutritional status and dietary patterns are associated with the risk of all-cause mortality and death from cancer and CCVD in people aged >60 years in the United States. Dietary patterns with high HEI and low DII were beneficial to health, whereas nutritional status needs to be maintained at a level that is not too low.

Breast cancer patients’ outcomes have improved dramatically in recent years, but relapses and poor prognosis remain common due to its aggressiveness and heterogeneity. The development of reliable biomarkers is still needed for predicting prognosis and treatment effectiveness. Recently, a growing body of research suggests that pseudouridine synthases contribute to the development of many cancers, but their contribution to breast cancer remains largely unknown. Using an integrative analysis, we selected pseudouridine synthase1(PUS1) as the candidate biomarker. A tissue microarray of 131 breast cancer patients was then utilized to determine the clinical significance and prognostic value of PUS1. RNA sequencing analysis was conducted to identify downstream genes that differ between control and PUS1 knockdown cells. The effect of PUS1 on phenotypes of cells was assessed using cell proliferation, colony formation, and transwell invasion assays. We found that breast tumors overexpressed PUS1 compared with paired normal tissues. PUS1 expression was positively correlated with triple-negative breast cancer (TNBC) status (P= 0.020) and tumor grade (P <0.0001), but not with age (P= 0.736), tumor size (P= 0.608), lymph node (P= 0.742), oestrogen receptor (ER) (P= 0.162), progesterone receptor (PR) (P= 0.901), human epidermal growth factor receptor 2 (HER2) (P= 0.608) or tumor stage (P= 0.411). Comparatively, patients with high PUS1 levels had shorter overall survival time (P=0.0001) and relapse-free survival time (P = 0.0093). A univariate and multivariate survival analysis suggested that the overall survival of patients was independently influenced by the PUS1 score (Univariate Cox P <0.0001, HR=5.176, 95% CI =2.420-11.07; Multivariate Cox P = 0.001, HR = 5.291, 95% CI =1.893-14.78). RNA sequencing data revealed the PUS1 knockdown significantly affects a series of cancer related biological process such as regulation of cell proliferation and cell migration, as well as KEGG pathways including Mitophagy and PI3K-Akt signaling. In vitro, knockdown of PUS1 significantly suppressed the proliferation and colony formation abilities of MDA-MB-231 cells and BT-549 cells. Additionally, the ability of tumor cells to invade was remarkably attenuated in low PUS1 expression groups compared with the corresponding control groups. Our results suggested that PUS1 is a novel biomarker that predicts poor outcomes in patients with breast cancer and may prove to be a promising treatment target.

Recurrence, metastasis, and drug resistance are still big challenges in breast cancer therapy. Internal and external stresses have been proven to substantially facilitate breast cancer progression through molecular and systemic mechanisms. For example, endoplasmic reticulum stress (ERS) results in activation of the unfolded protein response (UPR), which are considered an important cellular stress response. More and more reports indicate its key role in protein homeostasis and other diverse functions involved in the process of breast cancer progression. Therefore, therapies targeting the activation of ERS and its downstream signaling pathways are potentially helpful and novel tools to counteract and fight breast cancer. However, recent advances in our understanding of ERS are focused on characterizing and modulating ERS between healthy and disease states, and so little attention has been paid to studying the role and clinical application of targeting ERS in a certain cancer. In this review, we summarize the function and main mechanisms of ERS in different molecular types of breast cancer, and focus on the development of agents targeting ERS to provide new treatment strategies for breast cancer.

Hong Zhu, Jin-Hai Tang, Shi-Meng Zhang, Jia-Ping Qian, Xin Ling, Xiao-Ying Wu, Ling-Xia Yang Department of Gastroenterology, Suzhou Ninth People’s Hospital, Suzhou, Jiangsu Province, People’s Republic of ChinaCorrespondence: Ling-Xia Yang Email ylxnjq@163.comBackground: Gastric cancer (GC) is a common cancer with high incidence and mortality worldwide. In recent years, accumulating evidence has shown that long noncoding RNAs (lncRNAs) exert critical roles in the development and progression of cancer by acting as a tumor initiator or suppressor. LINC00963 is a newly reported lncRNA related to cancer, and its role in GC remains unclear.Materials and Methods: The expression levels of LINC00963, miR-612, and cell division cycle 5-like protein (CDC5L) were measured using quantitative real-time PCR or Western blot. The biological functions of LINC00963, miR-612, and CDC5L in GC cells were analyzed by transwell and proliferation experiments. The expression of CDC5L in patients with GC was evaluated using the Oncomine database. Bone marrow-derived dendritic cells (DCs) were derived from C57BL/6 mice.Results: LINC00963 expression was higher in GC tissues than in adjacent normal tissues. Similar results were found in GC cell lines and normal human gastric epithelial cells. Upregulation of LINC00963 was related to the poor prognosis of patients with GC. Knockdown of LINC00963 inhibited the proliferation, invasion, and metastasis but promoted the apoptosis of GC cells. Furthermore, silencing of LINC00963 in GC cells significantly suppressed the tumor growth of GC. Bioinformatics analysis indicated that LINC00963 could target miR-612 by functioning as a competing endogenous RNA. The expression of miR-612 decreased in GC tissues and cell lines. Meanwhile, LINC00963 expression was negatively associated with miR-612. CDC5L was a direct target of miR-612. miR-612 suppressed the expression of CDC5L in GC tissues and cells. Moreover, LINC00963 inhibited the differentiation and maturation of DCs by regulating miR-612 expression in DCs.Conclusion: LINC00963 promoted the progression of GC by competitively binding to miR-612 to regulate the expression of CDC5L and mediated DC-related anti-tumor immune response. Thus, targeting LINC00963 may be a promising therapeutic strategy for GC.Keywords: lncRNA LINC00963, gastric cancer, miR-612, CDC5L, dendritic cells

Background Never in Mitosis (NIMA)-related kinase 2 (Nek2), a member of the serine/threonine kinase family, localizes to centrosomes/kinetochores, which was involved in mitotic regulation. However, the clinical significance and the role of NEK2 in various cancers remained largely elusive. Methods ONCOMINE, Tumor Immune Estimation Resource (TIMER), Kaplan-Meier plotter database, UALCAN, GeneMANIA, String and CancerSEA Analysis were used to fully evaluate the clinical value of NEK2 Results NEK2 was meaningfully up-regulated in the vast majority of cancers, however, the prognostic significance of NEK2 was only associated with the patients with breast cancer, lung cancer, liver cancer, renal carcinoma, pancreatic ductal adenocarcinoma, sarcoma and thyroid carcinoma. Furthermore, NEK2 expression was also correlated with individual pathological cancer stages. In addition, NEK2 participated in regulating the tumor immunity. Enrichment analysis and functional state showed NEK2 was involved in the cell cycle. Conclusions These findings interpret the clinic value of NEK2 in a variety of cancers, which may be a novel biomarker and therapeutic target.

Triple negative breast cancer (TNBC) refers to a special subtype of breast cancer that is negative for the estrogen receptor, the progesterone receptors, and human epidermal growth factor receptor 2. As a group of diseases, it has strong heterogeneity. Refractory metastatic triple negative breast cancer (mTNBC) has even greater heterogeneity, more susceptibility to drug resistance, and faster progression, which makes it more difficult to treat effectively and significantly reduces a patient's overall survival. Therefore, in order to overcome this difficulty in clinical practice, we need to deeply understand the special subgroup by analyzing definition and prognostic factors of refractory mTNBC and describing the therapeutic status and future treatment directions.Recent domestic and foreign guidelines, as well as clinical studies related to refractory mTNBC on PubMed and the China National Knowledge Infrastructure (CNKI) databases were retrospectively analyzed. The six keywords we selected were used for literature search. Two authors performed database searches independently, and disagreements over the results were mediated by a third reviewer.According to the guidelines, refractory mTNBC has not been clearly defined. Related studies indicated that tumor heterogeneity may be one of the main mechanisms of early relapse or drug resistance in refractory mTNBC. The clinical treatment options for refractory mTNBC are very limited. Although chemotherapy is the standard treatment, it is limited by poor efficacy and intolerance in the clinical stage. Therefore, in recent years, many studies have explored novel treatment options. Both immunotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors have been selected as first-line treatment in clinical studies, but gained limited benefits. Indeed, clinical studies have shown good efficacy with novel ADCs, which may be promising in the clinical treatment of refractory mTNBC.Currently, improving the survival time and quality of life of refractory mTNBC are major challenges for clinicians. Novel therapies including immunosuppressive agents, PARP inhibitors, and ADCs rather than chemotherapy alone have achieved good results in the exploration of first-line treatment for refractory TNBC patients, but this warrants further research and investigation.

More initial clinical node-positive breast cancer patients achieve axillary pathological complete response (ax-pCR) after neoadjuvant systemic therapy (NST). Restaging axillary status and performing de-escalated surgical procedures to replace routine axillary lymph nodes dissection (ALND) is urgently needed. Targeted axillary lymph node biopsy (TLNB) is a novel de-escalated surgical strategy marking metastatic axillary nodes before NST and targeted dissection and biopsy intraoperatively to tailor individual axillary management.This study provided a systematic review and meta-analysis to evaluate the feasibility and diagnosis accuracy of TLNB. Prospective and retrospective clinical trials on TLNB were searched from Pubmed, Embase, and Cochrane. Identification rate (IFR), false-negative rate (FNR), negative predictive value (NPV), and rate of ax-pCR were the outcomes of this meta-analysis.One thousand nine hundred and twenty patients attempted TLNB, with an overall IFR of 93.5% (95% confidence interval [CI] 90.1%-96.2%). IFR of three nodal marking methods, namely iodine seeds, clips, and carbon dye, was 95.6% (95% CI 91.2%-98.7%), 91.7% (95% CI 87.3%-95.4%), and 97.1% (95% CI 89.1%-100.0%), respectively. Of them, 847 patients received ALND, with an overall FNR of 5.5% (95% CI 3.3%-8.0%), and NPV ranged from 90.1% to 96.1%. Regression analysis showed that the overlap of targeted and sentinel biopsied nodes might associate with IFRs and FNRs.TLNB is a novel, less invasive surgical approach to distinguish initial node-positive breast cancer that achieves negative axillary conversion after NST. It yields an excellent IFR with a low FNR and a high NPV. A combination of preoperative imaging, intraoperative TLNB with SLNB, and postoperative nodal radiotherapy might affect the future treatment paradigm of primary breast cancer with nodal metastases.

Purpose: This study aimed to explore the role of N6-methyladenosine (m6A)-related lncRNAs in lung adenocarcinoma (LUAD). Methods: Gene expression data and clinical data of LUAD patients were acquired from The Cancer Genome Atlas (TCGA) Database. Combined with clinical information, the prognostic m6A-related lncRNAs were identified through differential lncRNA expression analysis and Spearman correlation analysis. Next, the least absolute shrinkage and selection operator (LASSO) regression was used to establish the prognostic risk model. We evaluated and validated the predictive performance of this model via survival analysis and receiver operating characteristic (ROC) curve analysis. The expression of immune checkpoints, immune cell infiltration and drug sensitivity of patients in different risk groups were analyzed separately. Results: A total of 19 prognostic m6A-related lncRNAs were identified and then the prognostic risk model was well established. The patients were divided into high- and low-risk group based on the median value of the risk scores. Compared with the patients in the low-risk group, the prognosis of the patients in the high-risk group was relatively poor. The ROC curves showed that this model had excellent sensitivity and specificity. Multivariate Cox regression analysis indicated that the risk score could be used as an independent prognostic risk factor. The expression levels of immune checkpoint CD276, PVR, and VTCN1 were significantly increased in the high-risk group. Finally, we found that the risk scores were correlated with immune cell infiltration and drug sensitivity. Conclusion: We constructed a prognostic risk model in LUAD patients based on m6A-related lncRNAs. This model was also associated with the expression of immune checkpoints, immune cell infiltration and drug sensitivity, which will provide new insights into immunotherapy for LUAD patients in the future.

Background. Tissue inhibitor of metalloproteinase-2 (TIMP2), an endogenous inhibitor of matrix metalloproteinases, has been disclosed to participate in the development and carcinogenesis of multiple malignancies. However, the prognosis of TIMP2 in different cancers and its correlation with tumor microenvironment and immunity have not been clarified. Methods. In this study, we conducted a comprehensive bioinformatics analysis to evaluate the prognostic and therapeutic value of TIMP2 in cancer patients by utilizing a series of databases, including Oncomine, GEPIA, cBioPortal, GeneMANIA, Metascape, and Sangerbox online tool. The expression of TIMP2 in different cancers was analyzed by Oncomine, TCGA, and GTEx databases, and mutation status of TIMP2 in cancers was then verified using the cBioPortal database. The protein-protein interaction (PPI) network of the TIMP family was exhibited by GeneMANIA. The prognosis of TIMP2 in cancers was performed though the GEPIA database and Cox regression. Additionally, the correlations between TIMP2 expression and immunity (immune cells, gene markers of immune cells, TMB, MSI, and neoantigen) were explored using Sangerbox online tool. Results. The transcriptional level of TIMP2 in most cancerous tissues was significantly elevated. Survival analysis revealed that an elevated expression of TIMP2 is associated with unfavorable survival outcome in multiple cancers. Enrichment analysis demonstrated the possible mechanisms of TIMPs and their associated genes mainly involved in pathways including extracellular matrix (ECM) regulators, degradation of ECM and ECM disassembly, and several other signaling pathways. Conclusions. Our findings systematically dissected that TIMP2 is a potential prognostic maker in various cancers and use the inhibitor of TIMP2, which may be an effective strategy for cancer therapy to improve the poor cancer survival and prognostic accuracy, but concrete mechanisms need to be validated by subsequent experiments.

Human epidermal growth factor receptor 2 (HER2)-positive is a particularly aggressive type of the breast cancer. Trastuzumab-based therapy is a standard treatment for HER2-positive breast cancer, but some patients are resistance to the therapy. There are no known diagnostic biomarkers to improve the early diagnosis of HER2-positive breast cancer and the clinical utility of trastuzumab therapy. Using ultrahigh-performance liquid time of flight mass spectrometry (UPLC-TOF-MS)-based serum metabolomics and multivariate statistical analysis, we investigated and identified the circulating metabolites L-arginine and arachidonic acid were elevated in trastuzumab-responsive and trastuzumab-resistant HER2-positive breast cancer patients, and increased until reaching their peaks in trastuzumab-resistant HER2-positive breast cancer patients. Moreover, an equation for assessing the risk scores based on linear logistic regression models involving L-arginine and arachidonic acid was created, which was beneficial for revealing metabolic changes in HER2-positive breast cancer and enhancing current trastuzumab-based therapy. In summary, we develop serum-based metabolic biomarkers for diagnosis of HER2-positive breast cancers and predicts the therapeutic effects of trastuzumab therapy.

Transmembrane p24 trafficking protein (TMED) family members are implicated in several solid tumors, but their clinical relevance for breast cancer (BC) remains unclear. This study aimed to probe their prognostic values and relations with tumor immunity in BC.TMED family mRNA expression was assessed in five microarray datasets (GSE65212, GSE42568, GSE5364, GSE22820 and GSE45827) from Gene Expression Omnibus (GEO) database and invasive breast cancer (BRCA) cohort from The Cancer Genome Atlas (TCGA). Receiver operating characteristic (ROC) curve was performed to determine the predictive values of filtered members of theBC tissues expressed

Exosomes are extracellular vesicles with unique membrane markers and components that participate in cellular communication. The contents of exosomes, including growth factors, microRNAs, long noncoding RNAs, and circular RNAs (circRNAs), have been recognized as prognostic biomarkers and promote cancer progression through cancer cell growth, metastasis, angiogenesis, and cancer development. One of the components of exosomes, circRNAs, are covalently closed and prevented from degrading, which results in their continually accumulating in exosomes. Evidence suggests that exosomal circRNAs are abundant and stable in body fluids and have been implicated in many diseases. In this article we summarize the biogenesis and function of circRNAs and explore the expressions of exosomal circRNAs in cancer, emphasizing the fact that exosomal circRNAs are a novel diagnostic biomarker in the early stages of cancer and/or a therapeutic target in further cancer treatment.

Background: Breast cancer is the most common cancer among women in China. Hence, how best to live with and improve the health-related quality of life (HRQoL) of this growing population of women is thus becoming of great public health importance. The aim of the study was to evaluate the relationship of lifestyle habits to HRQoL among younger and older women who were initially diagnosed with breast cancer within the first two weeks, determine the contribution of lifestyle habits factors on HRQoL.Methods: A multi-center, hospital-based, case control study was conducted among breast cancer women from 22 hospitals in 11 provinces or municipalities in northern and eastern China from April 2012 to April 2013. The Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) simplified Chinese version 4 was used to measure HRQoL. Chi-square test, ANOVA and Multivariable generalized linear models were conducted to verify differences in HRQoL between two groups and to evaluate the contribution of lifestyle habits factors ( including smoking, passive smoking, alcohol intake, Tea, Coffee, Sleep satisfaction, Current life satisfaction, Physical activity, BMI) on HRQoL of breast cancer patients.Results: 1199 eligible breast cancer patients were used for analysis. Younger women (age Conclusion: The relationship of the nine lifestyle habit items to HRQoL were different between younger and older women. Associated variable of low HRQoL can help clinicians take intervention early in order to improve the prognosis of breast cancer patients.

Background/Aims: Treatment of breast cancer remains a clinical challenge. This study aims to validate exosomal microRNA-1246 (miR-1246) as a serum biomarker for breast cancer and understand the underlying mechanism in breast cancer progression. Methods: The expression levels of endogenous and exosomal miRNAs were examined by real time PCR, and the expression level of the target protein was detected by western blot. Scanning electron and confocal microscopy were used to characterize exosomes and to study their uptake and transfer. Luciferase reporter plasmids and its mutant were used to confirm direct targeting. Furthermore, the functional significance of exosomal miR-1246 was estimated by invasion assay and cell viability assay. Results: In this study, we demonstrate that exosomes carrying microRNA can be transferred among different cell lines through direct uptake. miR-1246 is highly expressed in metastatic breast cancer MDA-MB-231 cells compared to non-metastatic breast cancer cells or non-malignant breast cells. Moreover, miR-1246 can suppress the expression level of its target gene, Cyclin-G2 (CCNG2), indicating its functional significance. Finally, treatment with exosomes derived from MDA-MB-231 cells could enhance the viability, migration and chemotherapy resistance of non-malignant HMLE cells. Conclusions: Together, our results support an important role of exosomes and exosomal miRNAs in regulating breast tumor progression, which highlights their potential for applications in miRNA-based therapeutics.

This study aimed to investigate risk factors associated with breast cancer among Han Chinese women in northern and eastern China. A matched case-control study involving 1489 patients with breast cancer and 1489 controls was conducted across 21 hospitals in 11 provinces in China, from April 2012 to April 2013. We developed a structured questionnaire to record information from face-to-face interviews with participants. Student's t-tests, Pearson's chi-square tests, and univariate and multivariate conditional logistic regression analyses were used to identify variables with significant differences between the case and control groups. Ten variables were identified (P

The aim of the present study was to investigate the efficacy of magnetic resonance imaging (MRI)-guided radiofrequency ablation (RFA) for breast cancer patients who cannot undergo traditional surgery. A total of 10 patients were treated by MRI-guided RFA, of whom 6 had stage IV disease (lung metastasis n=3, bone metastasis n=1, liver metastasis n=1 and mediastinal metastasis n=1) and the remaining 4 patients, who refused surgery, had stage III disease accompanied by severe underlying conditions. The changes in feasibility, tumor volume, bleeding, local recurrence, metastasis and complications were evaluated after RFA. The patients were followed up at 1, 3, 6 and 12 months, and annually thereafter. A total of 14 RFA sessions were successfully performed (100%) in the 10 patients, among whom 7 patients underwent a single RFA session, 2 patients underwent two sessions, and 1 patient underwent three sessions. Compared with pre-RFA, the volume of the tumors at 6 months after RFA was markedly decreased. There was no local tumor recurrence or metastasis detected during a mean follow-up period of 19.5±3.46 months, and no major complications were reported. Therefore, RFA was found to be a minimally invasive and feasible treatment method in the present study, and MRI-guided RFA may be a promising alternative option for breast cancer patients who are unable to tolerate surgery. However, more prospective studies on the applicability of RFA in breast cancer are required.

Paclitaxel has been widely used in the treatment of breast cancer. However, the development of drug resistance often increases the failure of chemotherapy. Growing evidence has reported the significant role of microRNAs (miRs) in drug resistance. The present study identified that miR-24 was significantly downregulated in paclitaxel-resistant (PR) breast cancer patients and in MCF-7/PR human breast carcinoma cells, and that overexpression of miR-24 could increase the effect of paclitaxel on drug-resistant breast carcinoma cells. Furthermore, miR-24 could directly bind to the 3'-untranslated region of ATP binding cassette B9 to downregulate its expression, thereby reducing drug transportation and improving the anti-tumor effect of paclitaxel on breast cancer cells. In vivo experiments also demonstrated that overexpression of miR-24 could increase the sensitivity of drug-resistant MCF-7 cells to paclitaxel. In conclusion, the present results suggested a novel function for miR-24 in reducing paclitaxel resistance in breast cancer, which may be of important clinical significance.

Transforming growth factor-β (TGF-β) signaling pathway is a key regulator of various cancer biologies, including cancer cell migration, invasion, angiogenesis, proliferation, as well as apoptosis, and it is one of indispensable signaling pathways during cancer metastasis. TGF-β signaling pathway can regulate and be regulated by a series of molecular and signaling pathways where microRNAs (miRNAs) seem to play important roles. miRNAs are small non-coding RNAs that can regulate expressions of their target genes. Emerging evidence suggest that miRNAs participate in various biological and pathologic processes such as cancer cells apoptosis, proliferation, invasion, migration, and metastasis by influencing multiple signaling pathways. In this article, we focus on the interaction between miRNAs and TGF-β in breast cancer (BC) metastasis through modulating invasion-metastasis-related factors, including epithelial-to-mesenchymal transition (EMT), cancer stem cells (CSCs), matrix metalloproteinase (MMP), tissue inhibitors of MMPs (TIMPs), cell adhesion molecules (CAMs), and tumor microenvironment (TME). Through a clear understanding of the complicated links between TGF-β pathway and miRNAs, it may provide a novel and safer therapeutic target to prevent BC metastasis.

Cancer susceptibility candidate 2 (CASC2), a long non-coding RNA (lncRNA), has been demonstrated to be a tumor suppressor in several types of cancer. However, the role and mechanism of CASC2 in breast cancer (BC) have not been investigated. In the present study, the expression and functions of CASC2 in BC were investigated. The expression of CASC2 was significantly decreased in BC tissues and cells compared with adjacent normal tissues and mammary epithelial cells, respectively. CASC2 overexpression inhibited the viability, migration and invasion, and elevated apoptosis of BC cells. In addition, CASC2 acted as a competing endogenous RNA for hsa-microRNA (miR)-96-5p and regulated the expression of its target gene, synoviolin (SYVN1). In miR-96-5p-overexpressed MDA-MB-231 cells, cell viability, migration and invasion was increased, and cell apoptosis was decreased, which was reversed by the upregulation of SYVN1. Taken together, the present study data indicated that decreased SYVN1 expression was a tumor suppressor, which inhibited the growth and metastasis of BC through the miR-96-5p/SYVN1 axis.

MicroRNAs (miRNAs) are small noncoding RNAs that could regulate gene expressions transcriptionally or post-transcriptionally through binding to 3' untranslated region (3'UTR) of target messenger RNAs (mRNAs), which were identified to be associated with tumorigenesis in various neoplasms. Among them, miR-101, encoded by two precursor transcripts (miR-101-1 and miR-101-2), was recognized to serve as a tumor suppressor via targeting critical oncogenes or anti-oncogenes. Additionally, studies have shown that miR-101 was participated in multiple cancer-related biological processes, including proliferation, apoptosis, angiogenesis, drug resistance, invasion and metastasis. In this review, we aim to summarize the function of miR-101 in different biological processes by figuring out the underlying target gene networks and explore its potential role as a biomarker in diverse neoplasms, which will provide a brand-new insight in molecular targeting cancer treatment.

Background This study was guided by principles of the theoretical system of evidence-based medicine. In particular, when searching for evidence of breast cancer, a measuring scale is an instrument for evaluating curative effects in accordance with the laws and characteristics of medicine and exploring the establishment of a system for medically assessing curative effects. At present, there exist few tools for evaluating curative effects. Patient- reported outcomes (PROs) refer to outcomes directly reported by patients (without input or explanations from doctors or other intermediaries) with respect to all aspects of their health. Data obtained from PROs provide evidence of treatment effects. Materials and methods In accordance with the tenets of theoretical medicine and ancient medical theory regarding breast cancer, principles for developing a PRO scale were established, and a theoretical model was developed and a literature review was performed, items from this pool were combined and split, and an initial scale was constructed. After a pilot survey and additional modifications, a pre-questionnaire scale was formed and used in a field investigation. After the application of statistical methods, the item pool was used to create a formal scale. The reliability, validity and feasibility of this formal scale were then assessed. Results In a clinical investigation, 479 responses were recovered, with an acceptance rate of 95%. a combination of various methods was employed, and the items that were selected by all methods or more than half of the methods were employed in the questionnaire. In these cases, the screening methods were combined with certain features of the item, A total of four domains and 38 items were reserved. The reliability analysis indicated that the PRO scale was relatively reliable. Conclusions Scientific assessment proved that the proposed scale exhibited good reliability and validity. This scale was readily accepted and could be used to assess the curative effects of medical therapy. However, given the limited scope of this investigation, the capacity for adapting this scale to incorporate other theories could not be determined.

The present study was performed to evaluate the therapeutic safety and feasibility of purse-string sutures with nylon loops and metal clips under single-channel endoscopy to repair gastrointestinal wall defects that had previously developed during endoscopic full-thickness resection (EFR). A multicenter prospective cohort study of 42 patients who had developed defects of the gastrointestinal wall during EFR was conducted from April 2012 to October 2016. All lesions were endoscopically repaired with either a single-channel gastroscope (research group, n=18) or double-channel gastroscope (control group, n=24). The patients' clinical features, purse-string suturing times and complication rates were analyzed. There was no significant difference in the perforation rate between the research and control groups. There were also no significant differences in the purse-string suturing time (research vs. control group, 10.5 vs. 14.6 min, respectively; P=0.214), specimen size or complication rate (subcutaneous emphysema) between the two groups. No recurrences were observed during the follow-up period. The current data suggest that application of purse-string sutures with nylon loops and metal clips for repair of EFR-induced gastrointestinal wall defects may be safely and feasibly applied under single-channel gastroscopy as well as under double-channel gastroscopy.

Sodium hydrosulfide (NaHS) is an exogenous hydrogen sulfide (H2S)-releasing molecule and has antitumor potential against a wide variety of human cancer types. The effect of exogenous H2S on the invasion of breast cancer and the possible underlying mechanisms remain unknown. The present study aimed to investigate the in vitro effects of H2S on transforming growth factor-β1 (TGF-β1)-induced human breast cancer cells and the associated mechanisms. MCF-7 cells were incubated with TGF-β1 to induce epithelial-mesenchymal transition (EMT) and an MTT assay was performed to detect cell viability. Flow cytometry, using propidium iodide (PI) staining, was used to determine the stages of the cell cycle. Apoptosis was detected with Annexin V-fluorescein isothiocyanate and PI double staining. Western blotting was performed to detect the protein expression of cystathionine γ-lyase (CSE, an endogenous H2S producer), phospho-p38 (a signaling protein associated with apoptosis), and SNAI1 (Snail, associated with the induction of EMT). A Boyden chamber invasion assay was performed to detect tumor invasion. The results demonstrated that when NaHS was administered to TGF-β1-treated MCF-7 cells, the cells exhibited decreased proliferation, G0/G1 phase cell cycle arrest and increased apoptosis. NaHS treatment following TGF-β1 administration also resulted in decreased cell invasion and decreased EMT, which was indicated by decreased Snail protein expression. In addition, incubation with NaHS increased endogenous CSE protein expression and decreased p38 mitogen-activated protein kinase phosphorylation in MCF-7 cells stimulated by TGF-β1. Furthermore, the inhibition of endogenous CSE by DL-propargylglycine increased EMT in the MCF-7 cells treated with NaHS and TGF-β1. In conclusion, the present study provides insights into a novel anticancer effect of H2S on breast cancer cells through activation of the CSE/H2S pathway and decreased expression of phospho-p38.

Extracellular vesicles have emerged as important mediators of intercellular communication and play an active role in cancer, including breast cancer. Despite limited studies, initial observations suggest that these vesicles are important in breast physiology and pathophysiology. We here, in brief, describe their potential use as future biomarkers and therapeutic agents in breast cancer. Extracellular vesicles in blood and breast fluid may have a great potential to detect and predict the presence of breast cancer, and extracellular vesicles modulation may emerge as a therapeutic approach in cancer therapy.

Estrogen receptor-α (ERα) is essential for estrogen-dependent growth and its level of expression is a crucial determinant of response to endocrine therapy and prognosis in ERα-positive breast cancer. Breast cancer patients show a wide range of ERα expression levels which change in individual patients during disease progression and in response to systemic therapies. However, little is known concerning how the expression of ERα is regulated in human breast cancer. Recently, several microRNAs (miRNAs) have been identified to regulate ERα expression and to predict ER, progesterone receptor (PR) and human epidermal growth factor 2 (HER2) status. The expression levels of miR-342 and ERα mRNA were analyzed in human breast cancer samples and cell lines by quantitative reverse transcription (RT)-PCR analysis. The correlations between the expression levels of miR-342 and clinicopathological factors were analyzed. Statistically significant associations were observed between miR-342 and ER, HER2 and vascular endothelial growth factor (VEGF) status in the human breast cancer samples and the levels of miR-342 gradually increased as ERα mRNA expression increased. Moreover, ectopic overexpression of miR-342 upregulated the expression levels of the ERα mRNA and significantly sensitized the MCF-7 cells to tamoxifen-induced apoptosis and inhibition of cellular proliferation. These results suggested that miR-342 expression is positively correlated with ERα mRNA expression in human breast cancer and that it may be a significant marker for predicting tamoxifen sensitivity in ERα-positive breast cancer and a potential target for restoring ERα expression and responding to antiestrogen therapy.

Objective The purpose of this study was to evaluate the impact of the negative lymph node (LN) count on the survival of the breast cancer patients in early stage after the axillary dissection.

Since the rate of persistence to adjuvant endocrine therapy such as 5-year aromatase inhibitors (AI) would decrease over time in patients with hormone-sensitive breast cancer, it is necessary to investigate if a patient support program could modify patients’ beliefs and improve their persistence to AI treatment. This was a prospective, multicenter, controlled, observational study to evaluate the efficacy of a patient support program in improving postmenopausal patients’ persistence to adjuvant AI medication for early stage breast cancer (NCT00769080). The primary objective was to compare the rates of 1-year persistence to upfront adjuvant AI for patients in the two observational arms (standard treatment group and standard treatment plus patient support program group). In this study, 262 patients were enrolled in the standard treatment group and 241 patients in the standard treatment plus patient support program group. The mean 1-year persistence rates were 95.9 and 95.8 % for the standard treatment group and the standard treatment plus patient support program group, respectively (P = 0.95). The mean times to treatment discontinuation were 231.2 days in the standard treatment group and 227.8 days in the standard treatment plus patient support program group, with no statistically significant difference between the two groups (P = 0.96). There was also no statistically significant difference in the reason for treatment discontinuation (P = 0.32). There was a significant relationship between the patient centered care questionnaire and poor persistence (odds ratio = 3.9; 95 % CI, 1.1–13.7; P = 0.035), suggesting that the persistence rate of patients with whom the doctor always or usually spends time is greater than that of patients with whom the doctor sometimes or never spends time. Patients’ persistence to adjuvant AI medication for postmenopausal, early stage breast cancer is relatively high in the first year and is not significantly increased by adding a patient support program to standard treatment.

Background The aim of this study is to investigate clinical significance of miR-155 expression in breast cancer. Methods TaqMan real-time RT-PCR was performed to detect miR-155 expression in breast cancer tissues. The correlation of miR-155 expression with clinicopathological factors and prognosis of breast cancer patients was analyzed. Then, the prognostic value of miR-155 expression was analyzed by univariate and multivariate analyses. Moreover, the effect of miR-155 expression on phenotypes of breast cancer cell was determined by antisense technology. Results The relative expression of miR-155 was significantly higher in breast cancer tissues than in corresponding nontumor tissues. High miR-155 expression was correlated with higher tumor grade, advanced tumor stage and lymph node metastasis (P = 0.012, 0.001, and 0.003, respectively). Kaplan–Meier survival analysis indicated that the disease-free and overall survival rates of high miR-155 group were significantly lower than those of low miR-155 group (P = 0.038 and 0.029, respectively). Multivariate analysis showed that high miR-155 expression was a poor prognostic factor (P = 0.009). Furthermore, antisense targeting miR-155 could inhibit growth, induce cell arrest in G0/G1 phase, enhance apoptosis, and increase radiosensitivity in breast cancer cells. Conclusions MiR-155 expression might be an independent prognostic factor and a therapeutic target for human breast cancer. J. Surg. Oncol. 2012; 106:260–266. © 2011 Wiley Periodicals, Inc.

The high resistant rate of Adriamycin (Adr) is associated with a poor prognosis of breast cancer in women worldwide. Since miR-222 might contribute to chemoresistance in many cancer types, in this study, we aimed to investigate its efficacy in breast cancer through PTEN/Akt/p27

Purpose of review Anthracyclines and taxanes are the two most active classes of cytotoxic agents that are commonly used for the treatment of breast cancer. However, resistance to these agents has become a major clinical obstacle. The aim of the present review is to define the roles of noncoding RNA (ncRNA) in breast cancer progression and the development of chemotherapy resistance. The ultimate goal is to exploit ncRNAs as new therapeutic tools to overcome resistance. Recent findings Two important types of ncRNA include microRNA (miRNA) and long noncoding RNA (lncRNA). Both miRNA and lncRNA have recently impacted the field of breast cancer research as important pieces in the mechanistic puzzle of the genes and pathways involved in breast cancer development and progression. Summary Herein, we review the roles of miRNA and lncRNA in breast cancer progression and the development of chemotherapy resistance. Future research should include identification of ncRNAs that could be potential therapeutic targets in chemotherapy-resistant tumors, as well as ncRNA biomarkers that facilitate more tumor-specific treatment options for chemotherapy-resistant breast cancer patients.

// Yue-Mei Xu 1, * , Hong-Jiang Wang 2, * , Fang Chen 3, * , Wan-Hua Guo 4, * , Yan-Yang Wang 4, * , Hang-Yu Li 5, * , Jin-Hai Tang 6, * , Ying Ding 1 , Ya-Chen Shen 7 , Min Li 1, 7 , Wen-Ying Xuan 1 , Lin-Hui Liu 1 , Jia Wang 2 , Xue-Rong Wang 1 , Ze-Jun Gao 1 , Xiu-Bin Liang 7 , Dong-Ming Su 1, 7, 8 1 State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China 2 Department of Breast Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, China 3 Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China 4 Department of Nuclear Medicine, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing, China 5 Department of General Surgery, 4th Affiliated Hospital, China Medical University, Shenyang, China 6 Department of General Surgery, The Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, China 7 Center of Metabolic Research, Nanjing Medical University, Nanjing, China 8 Center of Cellular therapy, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China * These authors have contributed equally to this work Correspondence to: Dong-Ming Su, e-mail: sudongming@njmu.edu.cn Keywords: HRD1, breast cancer, metastasis, IGF-1R, degradation Received: May 02, 2015 Accepted: October 09, 2015 Published: October 19, 2015 ABSTRACT HRD1 (3-hydroxy-3-methylglutaryl reductase degradation) is an E3 ubiquitin ligase. We found that HRD1 was significantly downregulated in 170 breast cancer tissues. Low tumoral HRD1 expression was correlated with clinicopathological characteristics and a shorter survival in breast cancer patients. P65 specifically bound to the HRD1 promoter and inhibited HRD1 expression. Suppression of NF-κB activity reversed IL-6-induced downregulation of HRD1 expression. HRD1 interacted with IGF-1R and promoted its ubiquitination and degradation by the proteasome. Overexpression of HRD1 resulted in the inhibition of growth, migration and invasion of breast cancer cells in vitro and in vivo . Furthermore, HRD1 attenuated IL-6-induced epithelial-mesenchymal transition in MCF10A cells. These findings uncover a novel role for HRD1 in breast cancer.