Signaling Pathway In Breast Cancer Research Articles

Flavonoids Targeting the mTOR Signaling Cascades in Cancer: A Potential Crosstalk in Anti-Breast Cancer Therapy.

Cancer is one of the leading causes of death worldwide. Breast cancer is the second leading cause of death in women, with triple-negative breast cancer being the most lethal and aggressive form. Conventional therapies, such as radiation, surgery, hormonal, immune, gene, and chemotherapy, are widely used, but their therapeutic efficacy is limited due to adverse side effects, toxicities, resistance, recurrence, and therapeutic failure. Many molecules have been identified and investigated as potential therapeutic agents for breast cancer, with a focus on various signaling pathways. Flavonoids are a versatile class of phytochemicals that have been used in cancer treatment to overcome issues with traditional therapies. Cell proliferation, growth, apoptosis, autophagy, and survival are all controlled by mammalian target of rapamycin (mTOR) signaling. Flavonoids target mTOR signaling in breast cancer, and when this signaling pathway is regulated or deregulated, various signaling pathways provide potential therapeutic means. The role of various flavonoids as phytochemicals in targeting mTOR signaling pathways in breast cancer is highlighted in this review.

MY11 exerts antitumor effects through activation of the NF-κB/PUMA signaling pathway in breast cancer

Breast cancer is the most common malignancy in women worldwide, and the discovery of new effective breast cancer therapies with lower toxicity is still needed. We screened a series of chalcone derivatives and found that MY11 ((E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-piperazinylphenyl) prop-2-en-1-one) had the strongest anti-breast cancer activity. MY11 inhibited the growth of MDA-MB-231 and MCF-7 breast cancer cells by arresting the cell cycle and promoting apoptosis, through regulation of the cell cycle and apoptosis-related proteins. PDTC (Pyrrolidinedithiocarbamate ammonium), a specific inhibitor of the NF-κB pathway, abolished the inhibitory effect of MY11 treatment. NF-κB has been shown to regulate PUMA-dependent apoptosis. Our in vitro studies demonstrated that MY11 promoted breast cancer cell apoptosis by activating the NF-κB/PUMA/mitochondrial apoptosis pathway (including Bcl-2, Bax, and Caspase-9). MY11 also inhibited tumor growth in an orthotopic breast cancer mouse model by inducing apoptosis through the NF-κB signaling pathway, importantly, with minimal toxicity. In addition, MY11 was found by docking analysis to bind to p65, which might enhance the stability of the p65 protein. Taken together, our findings indicate that MY11 exerts a significant anticancer effect in breast cancer and that it may be a potential candidate for the treatment of breast cancer.

Development and Validation of a Novel PPAR Signaling Pathway-Related Predictive Model to Predict Prognosis in Breast Cancer.

This study is aimed at exploring the potential mechanism of the PPAR signaling pathway in breast cancer (BRCA) and constructing a novel prognostic-related risk model. We used various bioinformatics methods and databases to complete our exploration in this research. Based on TCGA database, we use multiple extension packages based on the R language for data conversion, processing, and statistics. We use LASSO regression analysis to establish a prognostic-related risk model in BRCA. And we combined the data of multiple online websites, including GEPIA, ImmuCellAI, TIMER, GDSC, and the Human Protein Atlas database to conduct a more in-depth exploration of the risk model. Based on the mRNA data in TCGA database, we conducted a preliminary screening of genes related to the PPAR signaling pathway through univariate Cox analysis, then used LASSO regression analysis to conduct a second screening, and successfully established a risk model consisting of ten genes in BRCA. The results of ROC curve analysis show that the risk model has good prediction accuracy. We can successfully divide breast cancer patients into high- and low-risk groups with significant prognostic differences (P = 1.92e − 05) based on this risk model. Combined with the clinical data in TCGA database, there is a correlation between the risk model and the patient's N, T, gender, and fustat. The results of multivariate Cox regression show that the risk score of this risk model can be used as an independent risk factor for BRCA patients. In particular, we draw a nomogram that can predict the 5-, 7-, and 10-year survival rates of BRCA patients. Subsequently, we conducted a series of pancancer analyses of CNV, SNV, OS, methylation, and immune infiltration for this risk model gene and used GDSC data to investigate drug sensitivity. Finally, to gain insight into the predictive value and protein expression of these risk model genes in breast cancer, we used GEO and HPA databases for validation. This study provides valuable clues for future research on the PPAR signaling pathway in BRCA.

Expert consensus on the clinical application of PI3K/AKT/mTOR inhibitors in the treatment of advanced breast cancer.

Phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB or AKT)/mammalian target of rapamycin (mTOR) signaling pathway (PAM pathway) plays an important role in the development of breast cancer and are closely associated with the resistance to endocrine therapy in advanced breast cancer. Therefore, anticancer treatment targeting key molecules in this signaling pathway has become a research hotspot in recent years. Randomized clinical trials have demonstrated that PI3K/AKT/mTOR inhibitors bring significant clinical benefit to patients with advanced breast cancer, especially to those with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER) 2-negative advanced breast cancer. Alpelisib, a PI3K inhibitor, and everolimus, an mTOR inhibitor, have been approved by FDA. Based on their high efficacy and relatively good safety profile, an expanded indication of everolimus in breast cancer has been approved by National Medical Products Administration (NMPA). Alpelisib is expected to be approved in China in the near future. The members of the consensus expert panel reached this consensus to comprehensively define the role of PI3K/AKT/mTOR signaling pathway in breast cancer, efficacy and clinical applications of PI3K/AKT/mTOR inhibitors, management of adverse reactions, and PIK3CA mutation detection, to promote the understanding of PI3K/AKT/mTOR inhibitors for Chinese oncologists, improve clinical decision-making, and prolong the survival of target patient population.

Polymer Nanoparticles Overcome Drug Resistance by a Dual-Targeting Apoptotic Signaling Pathway in Breast Cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activating therapy has received wide attention due to its capacity to precisely induce cancer cell apoptosis. However, drug resistance and the poor pharmacokinetic properties of TRAIL protein are obstacles in TRAIL-based therapy for cancer. Herein, a strategy is developed to remotely control and specifically initiate TRAIL-mediated apoptotic signaling to promote TRAIL-resistant cancer cell apoptosis using near-infrared (NIR) light-absorbing conjugated polymer nanoparticles (CPNs). Upon 808 nm laser excitation, the promoter 70 kilodalton heat shock protein (HSP70) initiates transcription of the TRAIL gene in response to heat shock, thereby expressing TRAIL protein in breast cancer cells, which activates the TRAIL-mediated apoptosis signaling pathway. Simultaneously, the CPNs locally release W-7, which targets calmodulin (CaM) and further promotes caspase-8 cleavage and enhances cancer cell apoptosis. Both in vitro and in vivo results demonstrate that CPNs/W-7/pTRAIL produces an excellent synergistic therapeutic effect on breast cancer upon near-infrared light with low toxicity. Therefore, this work provides a strategy for overcoming drug resistance through dual-targeting TRAIL-mediated apoptotic signaling in breast cancer.

DNMT3A and DNMT3B in Breast Tumorigenesis and Potential Therapy.

Breast cancer has become a leading cause of cancer-related deaths in women worldwide. DNA methylation has been revealed to play an enormously important role in the development and progression of breast cancer. DNA methylation is regulated by DNA methyltransferases (DNMTs), including DNMT1, DNMT2, and DNMT3. DNMT3 family has three members: DNMT3A, DNMT3B, and DNMT3L. The roles and functions of DNMT1 in breast cancer have been well reviewed. In this article, the roles of DNMT3A and DNMT3B in breast tumorigenesis and development are reviewed. We also discuss the SNP and mutations of DNMT3A and DNMT3B in breast cancer. In addition, we summarize how DNMT3A and DNMT3B are regulated by non-coding RNAs and signaling pathways in breast cancer, and targeting the expression levels of DNMT3A and DNMT3B may be a promising therapeutic approach for breast cancer. This review will provide reference for further studies on the biological functions and molecular mechanisms of DNMT3A and DNMT3B in breast cancer.

Long non-coding RNA HOTAIR induces the PI3K/AKT/mTOR signaling pathway in breast cancer cells.

The phosphoinositide 3-kinase/protein kinase AKT/mammalian target of rapamycin signaling pathway is essential for proper cellular metabolism and cell growth. However, aberrant activation of this pathway has been linked to the progression and metastasis of breast cancer. Recently, the role of long non-coding RNAs in interfering with the cell signaling pathways involved in cell growth and metabolism has been identified. HOX antisense intergenic RNA is an long non-coding RNA whose abnormal expression has been associated with development, therapy resistance, and metastasis of breast cancer. The purpose of this study was to investigate whether the long non-coding RNA HOX antisense intergenic RNA is linked to the phosphoinositide 3-kinase/protein kinase AKT/mammalian target of rapamycin signaling pathway in breast cancer cells. HOX antisense intergenic RNA was silenced in the breast cancer cell line MCF-7 using siRNAs. Subsequently, the gene expression level of HOX antisense intergenic RNA, PI3K, AKT, and mTOR was assessed using real-time RT-PCR. Also, the 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl-tetrazolium bromide) assay was used to analyze cell proliferation. The results revealed that HOX antisense intergenic RNA knockdown can downregulate the expression of PI3K, AKT, and mTOR RNAs compared to negative control in MCF-7 cells. In addition, the proliferation of breast cancer cells was significantly reduced following the HOX antisense intergenic RNA silencing. This study may introduce HOX antisense intergenic RNA as a molecule involved in the upregulation of the phosphoinositide 3-kinase/protein kinase AKT/mammalian target of rapamycin signaling pathway in breast cancer cells that may contribute to breast cancer cell proliferation.

Overexpression of microRNA-145 enhanced docetaxel sensitivity in breast cancer cells via inactivation of protein kinase B gamma-mediated phosphoinositide 3-kinase -protein kinase B pathway

ABSTRACT Chemoresistance is a major challenge for the treatment of breast cancer (BC). Previous studies showed that miR-145 level decreases in chemoresistant BC tissues. Nevertheless, the biological function of miR-145 on docetaxel resistance of BC cells remains unclear, which is what our research attempted to clarify. RT-qPCR analyzed miR-145 level, and cell viability and colony formation assays assessed the impact of miR-145 on docetaxel resistance. Molecular mechanisms of miR-145-mediated docetaxel sensitivity were examined by Luciferase reporter assay and Western Blot assessed the function of AKT3 and PI3K/AKT signaling. Our research found that miR-145 expression presented significant downregulation in docetaxel-resistant BC cells. Meanwhile, miR-145 overexpression facilitated the docetaxel sensitivity of BC cells in vivo and in vitro, while the miR-145 inhibitor decreased the sensitivity of BC cells to docetaxel. We also observed that miR-145 inhibited docetaxel resistance mainly via downregulation of the AKT3 expression and further inhibited PI3K/AKT pathway. To conclude, this research provides a novel strategy for improving chemosensitivity through the newly identified miR-145-AKT3/PI3K-AKT signaling pathway in BC.

MiR-217-5p suppresses epithelial-mesenchymal transition and the NF-κB signaling pathway in breast cancer via targeting of metadherin.

MicroRNAs (miRNAs) have been associated with a number of human malignancies, including breast cancer (BC). However, the expression, biological function and fundamental underlying mechanism of miR-217-5p in BC remain unclear. Therefore, in the present study, the expression levels of miR-217-5p and metadherin (MTDH) were examined in BC tissues and BC cell lines using reverse transcription-quantitative PCR. Cell Counting Kit-8 assays, cell proliferation, wound healing assays, Transwell assays and western blotting were used to examine the effects of miR-217-5p on cell proliferation, migration, the epithelial-mesenchymal transition (EMT) and NF-κB signaling pathway expression. The direct relationship between miR-217-5p and MTDH was assessed using a dual-luciferase reporter assay. The results demonstrated that significantly reduced expression levels of miR-217-5p but significantly increased mRNA expression levels of MTDH were observed in BC tissues from 35 patients with BC compared with non-tumor breast tissues. Furthermore, BC cell lines SK-BR3 and BT549 expressed miR-217-5p at markedly lower levels and MTDH at markedly higher levels compared with the breast epithelial MCF10A cell line. miR-217-5p overexpression significantly inhibited cell proliferation, invasion and migration and suppressed the EMT in BC cells. miR-217-5p overexpression also inhibited the NF-κB signaling pathway by markedly decreasing p65 mRNA and protein expression levels but significantly increasing IκBα expression levels. Furthermore, miR-217-5p knockdown markedly increased MTDH mRNA and protein expression levels. The expression levels of miR-217-5p were negatively correlated with those of MTDH in BC tissues. These results suggested that restoration of MTDH expression levels could potentially attenuate the inhibitory effects of miR-217-5p overexpression on BC cell proliferation. Therefore, in conclusion miR-217-5p overexpression may inhibit cell migration, invasion, the EMT and NF-κB signaling pathway in BC via targeting of MTDH. miR-217-5p may serve as an important potential target in BC therapy.

Systemic Efficacy of Sirolimus via the ERBB Signaling Pathway in Breast Cancer

Rapamycin, also known as sirolimus, inhibits the mTOR pathway in complex diseases such as cancer, and its downstream targets are ribosomal S6 kinases (RPS6K). Sirolimus is involved in regulating cell growth and cell survival through roles such as the mediation of epidermal growth factor signaling. However, the systemic efficacy of sirolimus in pathway regulation is unclear. The purpose of this study is to determine systemic drug efficacy using computational methods and drug-induced datasets. We suggest a computational method using gene expression datasets induced by sirolimus and an inverse algorithm that simultaneously identifies parameters referring to gene–gene interactions. We downloaded two sirolimus-induced microarray gene expression datasets and used a computational method to obtain the most enriched pathway, then adopted an inverse algorithm to discover the gene–gene interactions of that pathway. In the results, RPS6KB1 was a target gene of sirolimus and was associated with genes in the pathway. The common gene interactions from two datasets were a hub gene, RPS6KB1, and 10 related genes (AKT3, CBLC, MAP2K7, NRG1/2, PAK3, PIK3CD/G, PRKCG, and SHC3) in the epidermal growth factor (ERBB) signaling pathway.

The Regulatory Role of Pivotal MicroRNAs in the AKT Signaling Pathway in Breast Cancer.

Breast cancer is the most prevalent type of cancer among women, and it remains the main challenge despite improved treatments. MicroRNAs (miRNAs) are a small non-coding family of RNAs that play an indispensable role in regulating major physiological processes, including differentiation, proliferation, invasion, migration, cell cycle regulation, stem cell maintenance apoptosis, and organ development. The dysregulation of these tiny molecules is associated with various human malignancies. More than 50% of these non-coding RNA sequences estimated have been placed on genomic regions or fragile sites linked to cancer. Following the discovery of the first signatures of specific miRNA in breast cancer, numerous researches focused on involving these tiny RNAs in breast cancer physiopathology as a new therapeutic approach or as reliable prognostic biomarkers. In the current review, we focus on recent findings related to the involvement of miRNAs in breast cancer via the AKT signaling pathway related to their clinical implications.

Zinc-finger protein 382 antagonises CDC25A and ZEB1 signaling pathway in breast cancer

Our previous studies found that Zinc-finger protein 382 (ZNF382) played as a tumor suppressor gene in esophageal and gastric cancers, and a positive correlation between the high expression of ZNF382 and better outcome in breast cancer patients. However, the biological roles and mechanisms of ZNF382 in breast cancer remains unclear. We detected ZNF382 expression by reverse-transcription PCR (RT-PCR) and real-time quantitative PCR (qRT-PCR) in breast cancer cells and tissues, and explored the impacts and mechanisms of ectopic ZNF382 expression in breast cancer cells in vitro and in vivo, respectively. Our results revealed that ZNF382 was significantly down-regulated in breast cancer tissues compared with adjacent non-cancer tissues. Restoration of ZNF382 expression in silenced breast cancer cells not only inhibited tumor cell colony formation, viability, migration and invasion, and epithelial-mesenchymal-transition (EMT), but also induced apoptosis and G0/G1 arrest. In conclusion, ZNF382 could induce G0/G1 cell cycle arrest through inhibiting CDC25A signaling, and, inhibit cell migration, invasion and EMT by antagonizing ZEB1 signaling in breast cancer cells.

Exosomal MicroRNA-204 Derived from Bone Marrow Mesenchymal Stem Cells (BMSCs) Inhibits Cell Proliferation and Induces Apoptosis Through NF-κB Signaling Pathway in Breast Cancer

Our study intends to assess the relationship between exosomes derived from bone marrow mesenchymal stem cells (BMSC-exo) and breast cancer. BMSC-exo were isolated and characterized by transmission electron microscopy. After transfection of BMSCs with miR-204 inhibitor, breast cancer cells were incubated with BMSC-exo followed by analysis of cell proliferation by CCK-8 assay, cell apoptosis by flow cytometry, and expression of apoptosis-related protein and NF-κB signaling by western blot. The co-culture of BMSC-exo with breast cancer cells enhanced miR-204 transcription, inhibited cell proliferation and induced apoptosis. Further, BMSC-exo accelerated apoptosis as demonstrated by the increased level of Bax and casepase-3 and decreased Bcl-2 expression, as well as reduced NF-κB signaling activity. But knockdown of miR-204 abolished the effect of BMSC-exo on apoptosis and proliferation with NF-κB signaling activation. In conclusion, miR-204 from BMSC-exo restrains growth of breast cancer cell and might be a novel target for treating breast cancer.

LncRNA-NEAT1/miR-148a-3p axis regulates cell viability, apoptosis and autophagy through wnt/β-catenin signaling pathway in Breast Cancer


 
 
 
 Purpose: Breast cancer has over the years been one of major acute carcinomas in women. This study investigated the fundamental mechanistic functions of the lncRNA-NEAT1/miR-148a-3p/Wnt/β-catenin axis in moderating cell viability, apoptosis and autophagy in Breast Cancer (BC).
 Methods: RT-qPCR measured expression of lncRNA NEAT1 and microRNA-148a-3p in human cell lines for Breast Cancer. Cell transfection upregulated or silenced the genes with CCK-8, western blot and FCM apoptosis assays determining the cellular growth, proliferation and protein expression related to autophagy biomarkers. Furthermore, luciferase assay analyzed the luciferase activity of lncRNA- NEAT1 and microRNA-148a-3p
 Results: The outcomes indicated that LncRNA-NEAT1 was upregulated in BC cell lines and promoted cell viability, autophagy and inhibited Apoptosis in BC cells. However, lncRNA-NEAT1 knockdown inhibited cell viability, autophagy and enhanced apoptosis. In addition, lncRNA-NEAT1 directly targeted microRNA-148a-3p. And, it was found that microRNA-148a-3p overturns the cellular viability, autophagy and inhibitory effects on Apoptosis imposed by lncRNA-NEAT1 overexpression. Lastly, overexpressed lncRNA-NEAT1 activated the Wnt/β-catenin regulatory network through sponging microRNA-148a-3p in BC cell lines.
 Conclusion: The present study showcased that lncRNA-NEAT1 could enhance tumor development in breast cancer via playing the role of molecular sponge to microRNA-148a-3p, and eventually hyper invigorating the Wnt/β-catenin regulatory network.
 
 
 

MiR-641 Inhibited Cell Proliferation and Induced Apoptosis by Targeting NUCKS1/PI3K/AKT Signaling Pathway in Breast Cancer.

Objective Studies revealed an important role of microRNAs (miRNAs) in multiple cancers, including breast cancer. In the present study, we evaluated the role and function of miR-641 in breast cancer. Methods The expression level of miR-641 in breast cancer cell lines (Hs-578T, MCF7, HCC1937, and MAD-MB-231) was determined by real-time PCR. Functional analyses, including CCK-8 assay, transwell assay, wound-healing assay, and apoptosis detection, were carried out to explore the roles of miRNA-641 in malignant behaviors of breast cancer. Luciferase report assay was used to investigate the regulatory association of miRNA-641 with its potential targets. Results The expression levels of miR-641 were downregulated, while the expression levels of nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) were increased in breast cancer cell lines. The in vitro results showed that miR-641 repressed proliferation and migration/invasion and promoted apoptosis of breast cancer cells. NUCKS1, a positive regulator of phosphatidylinositol-3-kinases (PI3K)/protein-serine-threonine kinase (AKT) pathway, was confirmed as a direct target of miR-641. The of treatment of the PI3K agonist, 740Y-P, could abrogate the antioncogenic potentials of miR-641 in breast cancer cells. Conclusion miR-641 functioned as a tumor suppressor through the PI3K/AKT signaling pathway via targeting NUCKS1 in breast cancer.

Nickel Doped Vanadium Pentoxide (Ni@V2O5) Nanocomposite Induces Apoptosis Targeting Pi3K/AKT/mTOR Signaling Pathway in Breast Cancer

Nickel Doped Vanadium Pentoxide (Ni@V2O5) Nanocomposite Induces Apoptosis Targeting Pi3K/AKT/mTOR Signaling Pathway in Breast Cancer

GRHL2 Expression Functions in Breast Cancer Aggressiveness and Could Serve as Prognostic and Diagnostic Biomarker for Breast Cancer.

Background:Breast cancer (BC) is the most frequent malignancy in women worldwide and the leading cause of female cancer–associated death in the world. Grainyhead-like 2 (GRHL2) is an important gene involved in human cancer progression. However, the role of GRHL2 in BC is unknown.Methods:In this study, we used in vitro experiments to verify the role of GRHL2 expression in BC progression. We used 14 databases to analyse the expression level of GRHL2 in BC and its prognostic and diagnostic value. In addition, the correlation between GRHL2 expression and immune cell infiltration and DNA methylation was also analysed.Results:At the cellular level, overexpression of GRHL2 induced E-cadherin expression in BC cells with a mesenchymal phenotype and resulted in a hybrid epithelial/mesenchymal (E/M) phenotype, which is more strongly correlated with tumour aggressiveness than a pure mesenchymal phenotype. Through analysis of various databases, we found that tumour tissue had a higher expression level of GRHL2. High expression of GRHL2 was associated with worse prognosis of BC patients and indicated that GRHL2 had significant diagnostic value. Grainyhead-like 2 is also related to immune infiltration and regulated by DNA methylation. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses showed that GRHL2-related signalling pathways in BC were related to tumour cell proliferation, invasion, and angiogenesis.Conclusions:In summary, evidence indicates that GRHL2 can be used as a prognostic and diagnostic biomarker for BC.

Lnc‑MICAL2‑1 sponges miR‑25 to regulateDKK3 expression and inhibits activation of theWnt/β‑catenin signaling pathway in breast cancer.

The Dickkopf3 (DKK3) protein antagonizes the Wnt receptor complex in the Wnt signaling pathway; however, to date, there have been no relevant studies investigating its upstream regulatory mechanism in breast cancer (BC), to the best of our knowledge. The present study aimed to explore whether long non‑coding RNA MICAL2‑1 (lnc‑MICAL2‑1) sponged microRNA (miR)‑25 to regulate DKK3 and inhibit activation of the Wnt/β‑catenin signaling pathway. The Atlas of non‑coding RNA in Cancer database was used to measure the expression levels of lnc‑MICAL2‑1 and their correlation with DKK3 expression levels. In addition, cell proliferation, invasion and migration were determined following the silencing or overexpression of lnc‑MICAL2‑1. The binding between lnc‑MICAL2‑1 and miR‑25, or miR‑25 and DKK3 was verified using RNA pull‑down and dual‑luciferase reporter assays. The effects of overexpression or knockdown of lnc‑MICAL2‑1 on DKK3 expression and the Wnt signaling pathway were further evaluated in a nude mouse xenograft model. The results revealed that, compared with in adjacent normal tissue, the expression levels of lnc‑MICAL2‑1 were downregulated in BC tissues, and the expression levels of lnc‑MICAL2‑1 were found to be positively correlated with DKK3 expression. The overexpression of lnc‑MICAL2‑1 in BC cells upregulated the mRNA expression levels of DKK3 and inhibited their proliferation. Results from the RNA pull‑down and dual luciferase reporter assays validated that lnc‑MICAL2‑1 could bind to miR‑25, which targets DKK3. The invivo experimental data demonstrated that lnc‑MICAL2‑1 inhibited tumor growth via regulating the Wnt signaling pathway. In conclusion, the findings of the present study highlighted a novel molecular mechanism through which lnc‑MICAL2‑1 may regulate the DKK3‑mediated Wnt signaling pathway in BC, highlighting potential targets for the treatment of the disease.

Development and Validation of a Novel Hypoxia-Related Long Noncoding RNA Model With Regard to Prognosis and Immune Features in Breast Cancer.

Background: Female breast cancer is currently the most frequently diagnosed cancer in the world. This study aimed to develop and validate a novel hypoxia-related long noncoding RNA (HRL) prognostic model for predicting the overall survival (OS) of patients with breast cancer. Methods: The gene expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database. A total of 200 hypoxia-related mRNAs were obtained from the Molecular Signatures Database. The co-expression analysis between differentially expressed hypoxia-related mRNAs and lncRNAs based on Spearman’s rank correlation was performed to screen out 166 HRLs. Based on univariate Cox regression and least absolute shrinkage and selection operator Cox regression analysis in the training set, we filtered out 12 optimal prognostic hypoxia-related lncRNAs (PHRLs) to develop a prognostic model. Kaplan–Meier survival analysis, receiver operating characteristic curves, area under the curve, and univariate and multivariate Cox regression analyses were used to test the predictive ability of the risk model in the training, testing, and total sets. Results: A 12-HRL prognostic model was developed to predict the survival outcome of patients with breast cancer. Patients in the high-risk group had significantly shorter median OS, DFS (disease-free survival), and predicted lower chemosensitivity (paclitaxel, docetaxel) compared with those in the low-risk group. Also, the risk score based on the expression of the 12 HRLs acted as an independent prognostic factor. The immune cell infiltration analysis revealed that the immune scores of patients in the high-risk group were lower than those of the patients in the low-risk group. RT-qPCR assays were conducted to verify the expression of the 12 PHRLs in breast cancer tissues and cell lines. Conclusion: Our study uncovered dozens of potential prognostic biomarkers and therapeutic targets related to the hypoxia signaling pathway in breast cancer.

Analysis and validation of m6A regulatory network: a novel circBACH2/has-miR-944/HNRNPC axis in breast cancer progression

BackgroundN6-methyladenosine (m6A), the most abundant and reversible modification of mRNAs in eukaryotes, plays pivotal role in breast cancer (BC) tumorigenesis and progression. Circular RNAs (circRNAs) can act as tumor promoters or suppressors by microRNA (miRNA) sponges in BC. However, the underlying mechanism of circRNAs in BC progression via regulating m6A modulators remains unclear.MethodsPrognostic m6A RNA methylation regulators were identified in 1065 BC patients from The Cancer Genome Atlas (TCGA) project. Differentially expressed (DE) miRNAs and DE circRNAs were identified between BC and normal samples in TCGA and GSE101123, respectively. MiRNA-mRNA interactive pairs and circRNA-miRNA interactive pairs were verified by MiRDIP and Circular RNA Interactome. GSEA, KEGG, and ssGSEA were executed to explore the potential biological and immune functions between HNRNPC-high and HNRNPC-low expression groups. qRT-PCR and Western blot were used to quantify the expression of HNRNPC and circBACH2 in MCF-7 and MDA-MB-231 cells. The proliferation of BC cells was assessed by CCK-8 and EdU assay.Results2 m6A RNA methylation regulators with prognostic value, including HNRNPC and YTHDF3, were identified in BC patients. Then, the regulatory network of circRNA-miRNA-m6A modulators was constructed, which consisted of 2 DE m6A modulators (HNRNPC and YTHDF3), 12 DE miRNAs, and 11 DE circRNAs. Notably, BC patients with high expression of HNRNPC and low expression of hsa-miR-944 were correlated with late clinical stages and shorter survival times. Besides, the results from the KEGG inferred that the DE HNRNPC was associated with the MAPK signaling pathway in BC. Moreover, the circBACH2 (hsa_circ_0001625) was confirmed to act as hsa-miR-944 sponge to stimulate HNRNPC expression to promote BC cell proliferation via MAPK signaling pathway, thus constructing a circBACH2/hsa-miR-944/HNRNPC axis in BC.ConclusionsOur findings decipher a novel circRNA-based m6A regulatory mechanism involved in BC progression, thus providing attractive diagnostic and therapeutic strategies for combating BC.