scholarly journals HMGA2 Supports Cancer Hallmarks in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5197
Author(s):  
Behzad Mansoori ◽  
Mikkel Green Terp ◽  
Ali Mohammadi ◽  
Christina Bøg Pedersen ◽  
Henrik Jørn Ditzel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Cancer Hallmarks ◽  
Protein Levels ◽  
Pathway Activation ◽  
Promising Target ◽  
Cancer Phenotypes

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that exhibits a high proliferation rate and early metastasis leading to a poor prognosis. HMGA2 is a DNA binding transcriptional regulator implicated in tumorigenesis. Here, we demonstrate that the HMGA2 promoter is demethylated in TNBC tumors, leading to increased expression of HMGA2 at both mRNA and protein levels. Importantly, high HMGA2 levels in TNBC tumors are correlated with poor prognosis. To detail the role of HMGA2 in TNBC development and progression, we studied its effect on core cancer phenotypes. Stable knockdown of HMGA2 in TNBC cells revealed that HMGA2 may support cell proliferation, cell migration and invasion. In addition, HMGA2 knockdown decreased cancer stem cell (CSC) features. Importantly, we found that silencing HMGA2 inhibited NF-kB signaling and lead to decreased expression of the downstream molecules IL-6 and IL-8 and reduced STAT3 pathway activation. Our results demonstrate that HMGA2 supports cancer hallmarks in TNBC and may represent a promising target for TNBC treatment.

scholarly journals MicroRNA-224 Promotes Tumorigenesis through Downregulation of Caspase-9 in Triple-Negative Breast Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Li Zhang ◽  
Xin Zhang ◽  
Xin Wang ◽  
Miao He ◽  
Shixing Qiao
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Direct Interaction ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines ◽  
Protein Levels ◽  
Reporter Assays ◽  
Novel Therapeutic Strategies

Triple-negative breast cancer (TNBC) harbors genetic heterogeneity and generally has more aggressive clinical outcomes. As such, there is urgency in identifying new prognostic targets and developing novel therapeutic strategies. In this study, miR-224 was overexpressed in breast cancer cell lines and TNBC primary cancer samples. Knockdown of miR-224 in MDA-MB-231 cancer cells reduced cell proliferation, migration, and invasion. Through integrating in silico prediction algorithms with KEGG pathway and Gene Ontology analyses, CASP9 was identified to be a potential target of miR-224. miR-224 knockdown significantly increased CASP9 transcript and protein levels. Furthermore, luciferase reporter assays confirmed a direct interaction of miR-224 with CASP9. Our findings have demonstrated that the miR-224/CASP9 axis plays an important role in TNBC progression, providing evidence in support of a promising therapeutic strategy for this disease.

scholarly journals Ribosome Proteins Represented by RPL27A Mark the Development and Metastasis of Triple-Negative Breast Cancer in Mouse and Human

2021 ◽  
Vol 9 ◽  
Author(s):  
Weipeng Zhao ◽  
Xichuan Li ◽  
Weiqi Nian ◽  
Jun Wang ◽  
Xiaorui Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Comparative Analysis ◽  
Ribosomal Protein ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Ribosomal Protein Genes ◽  
Gene Profiles

Triple-negative breast cancer (TNBC) is known to have a poor prognosis and limited treatment options. The lack of targeted therapies and poor prognosis of patients with TNBC have made it urgent to discover novel critical diagnosis and therapeutic targets in the TNBC field. Here, in the current study, we integrated the single-cell RNA-sequencing (scRNA-seq) data from four normal mouse mammary tissues and four mouse breast tumors. Comparative analysis was conducted to identify the gene profiles of normal epithelial cells and cancer cells at different models. Surprisingly, two ribosomal protein genes, Rpl27a and Rpl15, were significantly upregulated in the cancer cells in all the TNBC models. Next, we accessed the scRNA-seq data from human primary and metastatic TNBC tissues, and comparative analysis revealed gene profiles of human primary and metastatic TNBC cancer cells. Ribosomal protein genes, represented by RPL27A and RPL15, showed significantly upregulated expression in metastatic TNBC cancer cells. Pathway analysis on the upregulated genes of the metastatic TNBC cancer cells identified the key regulators and signaling pathways that were driving the metastasis of the TNBC cancer cells. Specifically, EIF2 signaling was significantly activated, and major member genes of this signaling pathway were upregulated. In vitro study revealed that targeting RPL27A or EIF2 signaling in a TNBC cell line, MDA-MB-231, significantly reduced cell migration and invasion. Altogether, these data suggested that the RPL27A gene is conducting critical functions in TNBC cancer development and metastasis and is a potential therapeutic target for TNBC.

scholarly journals Overexpression of EZH2/NSD2 Histone Methyltransferase Axis Predicts Poor Prognosis and Accelerates Tumor Progression in Triple-Negative Breast Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Bo Gao ◽  
Xiumin Liu ◽  
Zhengjin Li ◽  
Lixian Zhao ◽  
Yun Pan
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Adenovirus Vector ◽  
Predictive Marker ◽  
Mitotic Cell ◽  
Migration And Invasion ◽  
Regulatory Relationship ◽  
Free Survival

Two histone methyltransferases, enhancer of zeste homolog 2 (EZH2) and nuclear SET domain-containing 2 (NSD2), are aberrantly expressed in several types of human cancers. However, the regulatory relationship between EZH2 and NSD2 and their prognostic values in breast cancer (BC) have not been fully elucidated. In this study, we demonstrated that EZH2 and NSD2 were overexpressed in BC compared with benign lesions and normal tissues using tissue microarray, immunohistochemistry, and bioinformatic databases. Both EZH2 and NSD2 expression were associated with pathological grade of tumor and lymph node metastasis. A comprehensive survival analysis using Kaplan-Meier Plotter database indicated that EZH2 expression was negatively correlated with relapse-free survival (RFS), overall survival (OS), distant metastasis-free survival (DMFS), and postprogression survival (PPS) in 3951 BC patients, and NSD2 expression was negatively correlated with RFS and DMFS. Notably, EZH2 and NSD2 expression were coordinately higher in triple-negative breast cancer (TNBC) than that in other subtypes. Stable knockdown of EZH2 using lentiviral shRNA vector significantly reduced the proliferation, migration and invasion abilities of TNBC cell line MDA-MB-231 and MDA-MB-468, and downregulated NSD2 expression as well as the levels of H3K27me3 and H3K36me2, two histone methylation markers catalyzed by EZH2 and NSD2, respectively. By contrast, overexpression of EZH2 using adenovirus vector displayed an inverse phenotype. Furthermore, knockdown of NSD2 in EZH2-overexpressing cells could dramatically attenuate EZH2-mediated oncogenic effects. Bioinformatic analysis further revealed the function and pathway enrichments of co-expressed genes and interactive genes of EZH2/NSD2 axis, suggesting that EZH2/NSD2 axis was associated with cell division, mitotic nuclear division and transition of mitotic cell cycle in TNBC. Taken together, EZH2/NSD2 axis may act as a predictive marker for poor prognosis and accelerate the progression of TNBC.

scholarly journals Down-regulated FST expression is involved in the poor prognosis of triple-negative breast cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sainan Liu ◽  
Bin Liu ◽  
Qian Zhao ◽  
Jikang Shi ◽  
Yulu Gu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Histological Grade ◽  
Univariate Analysis ◽  
Regulatory Protein ◽  
Young Patients ◽  
Migration And Invasion

Abstract Background Triple-negative breast cancer (TNBC) is more commonly associated with young patients, featuring high histological grade, visceral metastasis, and distant recurrence. Follistatin (FST) is a secreted extracellular regulatory protein that antagonizes TGF-β superfamily such as activin and TGF-β related superfamily such as bone morphogenetic protein (BMP). The implication of FST in the proliferation, angiogenesis, and metastasis of solid tumors documents good or poor outcome of patients with BC. However, the role of FST in TNBC remains unclear. Methods Data of 935 patients with breast cancer (BC) were extracted from TCGA. Case–control study, Kaplan–Meier, uni-multivariate COX, and ROC curve were utilized to investigate the relationship between FST expression and the clinical characteristics and prognosis of BC. Functional studies were used to analyze the effect of FST expression on proliferation, apoptosis, migration, and invasion of TNBC cell lines. Bioinformatic methods such as volcanoplot, GO annd KEGG enrichment, and protein–protein interactions (PPI) analyses were conducted to further confirm the different roles of FST in the apoptotic pathways among mesenchymal and mesenchymal stem-like cells of TNBC. Results Data from TCGA showed that low FST expression correlated with poor prognosis (for univariate analysis, HR = 0.47, 95% CI: 0.27–0.82, p = 0.008; for multivariate analysis, HR = 0.40, 95% CI: 0.21–0.75, p = 0.004). Low FST expression provided high predicted value of poor prognosis in TNBC amongst BCs. FST knockdown promoted the proliferation, migration and invasion of BT549 and HS578T cell lines. FST inhibited the apoptosis of mesenchymal cells by targeting BMP7. Conclusions Low FST expression is associated with poor prognosis of patients with TNBC. FST expressions exhibit the anisotropic roles of apoptosis between mesenchymal and mesenchymal stem-like cells but promote the proliferation, migration, invasion in both of two subtypes of TNBC in vitro. FST may be a subtype-heterogeneous biomarker for monitoring the progress of TNBC.

scholarly journals Dasatinib/Celecoxib combination: A new hope in triple negative breast cancer treatment

2021 ◽  
Author(s):  
Nermine Aly Moussa ◽  
Mahira Mohamed ◽  
Medhat Haroun ◽  
Maged Helmy Wasfy
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Triple Negative Breast Cancer ◽  
Caspase 3 ◽  
Triple Negative ◽  
Signaling Cascades ◽  
Migration And Invasion ◽  
Protein Levels ◽  
Cox 2 ◽  
Active Caspase

Abstract Despite the tremendous efforts to implement new paradigms for breast cancer, the disease still remains a major challenge worldwide. Genetic deregulation is evident in all breast cancer subtypes and comprises a multitude of mutated genes and deregulated signaling cascades. In this sense, co-targeting Src and COX-2 signaling cascades have attracted fervent interest. This work explored the probable anti-carcinogenic effects of Dasatinib as a Src inhibitor, Celecoxib as a selective COX-2 inhibitor, and their combination in MDA-MB-231 triple-negative breast cancer cell line. Drug growth inhibition 50 (GI50) was determined using the MTT assay and the obtained results were analyzed using CompuSyn 3.0.1 software. MDA-MB-231 cells were divided into four treatment groups including a positive control, Dasatinib-treated, Celecoxib-treated, and combination-treated groups. Standard sandwich ELISA was used for the determination of the protein levels of c-Src, Bcl-2, p-AKT, FAK, PGE2, VEGF, and cyclin D1. Active caspase-3 was determined colorimetrically and the expression of COX-2 and c-Src genes was quantitatively determined via quantitative real-time polymerase chain reaction. The GI50 for Dasatinib was 0.05699 µM while that for Celecoxib was 69.0976 µM. Dasatinib up-regulated c-Src gene while Celecoxib and Dasatinib/Celecoxib combination down-regulated such expression level. COX-2 gene was down-regulated by Celecoxib while it was up-regulated by both Dasatinib and Dasatinib/Celecoxib combination. On one hand, Dasatinib, Celecoxib, and their combination significantly reduced the protein levels of c-Src, Bcl-2, p-AKT, FAK, PGE2, VEGF, and cyclin D1. On the other hand, they elevated active caspase-3. To sum up, Dasatinib/Celecoxib combination increased the capability for apoptosis and suppressed proliferation, angiogenesis, migration, and invasion suggesting a strong cross-talk between Src signaling cascade and COX-2/PGE2 via the intermediate PI3K/AKT/mTOR pathway. Further in-vitro and in-vivo studies are warranted to verify the present findings.

scholarly journals MiR-26b-5p inhibits cell proliferation and EMT by targeting MYCBP in triple-negative breast cancer

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Sugang Ma ◽  
Hui Wei ◽  
Chunyan Wang ◽  
Jixia Han ◽  
Xiumin Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Ectopic Expression ◽  
Suppressive Effect ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Protein Levels ◽  
Tnbc Cell

Abstract Background The study was designed to elucidate the association and functional roles of miR-26b-5p and c-MYC binding protein (MYCBP) in triple-negative breast cancer (TNBC). Method Luciferase reporter assay was used to confirm the relationship between miR-26b-5p and MYCBP in TNBC cells. The expression levels of miR-26b-5p and MYCBP in tissue specimens and cell lines were determined using reverse transcription-quantitative PCR. Cell proliferation, migration and invasion were assessed using CCK-8 assay, colony formation and transwell assay. Results We first observed that miR-26b-5p directly targets the 3′-UTR of MYCBP to inhibit MYCBP expression in MDA-MB-468 and BT-549 cells. The expression of miR-26b-5p was inversely correlated with MYCBP expression in TNBC tissues. We further demonstrated that MYCBP knockdown suppressed the proliferation, migration and invasion of TNBC cells. Furthermore, MYCBP overexpression counteracted the suppressive effect of miR-26b-5p on TNBC cell behaviors. Western blot analysis demonstrated that the E-cadherin protein level was increased, while protein levels of N-cadherin and vimentin were decreased in cells transfected with miR-26b-5p, which were all reversed by ectopic expression of MYCBP. Conclusions In summary, our findings revealed the tumor suppressive role of miR-26b-5p in regulating TNBC cell proliferation and mobility, possibly by targeting MYCBP.

scholarly journals New Insights into the Implication of Epigenetic Alterations in the EMT of Triple Negative Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 559 ◽  
Author(s):  
Khaled ◽  
Bidet
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Modifications ◽  
Migration And Invasion ◽  
Epigenetic Alterations ◽  
Mesenchymal Transition ◽  
Metastatic Relapse

Breast cancer is the most common cancer and leading cause of cancer death among women worldwide, encompassing a wide heterogeneity of subtypes with different clinical features. During the last two decades, the use of targeted therapies has emerged in clinical research in order to increase treatment efficiency, improve prognosis and reduce recurrence. However, the triple negative breast cancer (TNBC) subtype remains a clinical challenge, with poor prognosis since no therapeutic targets have been identified. This aggressive breast cancer entity lacks expression of oestrogen receptor (ER) and progesterone receptor (PR), and it does not overexpress human epidermal growth factor receptor 2 (HER2). The major reason for TNBC poor prognosis is early therapeutic escape from conventional treatments, leading to aggressive metastatic relapse. Metastases occur after an epithelial-mesenchymal transition EMT of epithelial cells, allowing them to break free from the primary tumour site and to colonize distant organs. Cancer-associated EMT consists not only of acquired migration and invasion ability, but involves complex and comprehensive reprogramming, including changes in metabolism, expression levels and epigenetic. Recently, many studies have considered epigenetic alterations as the primary initiator of cancer development and metastasis. This review builds a picture of the epigenetic modifications implicated in the EMT of breast cancer. It focuses on TNBC and allows comparisons with other subtypes. It emphasizes the role of the main epigenetic modifications lncRNAs, miRNAs, histone and DNA- modifications in tumour invasion and appearance of metastases. These epigenetic alterations can be considered biomarkers representing potential diagnostic and prognostic factors in order to define a global metastatic signature for TNBC.

scholarly journals Overexpression of SERPINA3 promotes tumor invasion and migration, epithelial-mesenchymal-transition in triple-negative breast cancer cells

Breast Cancer ◽  
2021 ◽  
Author(s):  
Yingzi Zhang ◽  
Jiao Tian ◽  
Chi Qu ◽  
Yang Peng ◽  
Jinwei Lei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Tnbc Cell

Abstract Background Recent studies have indicated that serpin peptidase inhibitor, clade A, member 3 (SERPINA3) is a potential marker associated with tumor progression, which connoted that SERPINA3 is related to malignant phenotypes in cancer. However, the biological function of SERPINA3 in breast cancer (BC) remains unclear. Methods Bioinformatics data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Immunohistochemical staining (IHC) was conducted to determine SERPINA3 expression. With strong aggressive abilities, triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, BT549 and MDA-MB-436) were obtained to examine SERPINA3 expression and functions. Wound healing and Transwell assays were performed to measure cell migration and invasion. Cell Counting Kit-8 (CCK-8) assay was conducted to detect cell proliferation abilities and cell viabilities. Results SERPINA3 was upregulated in BC tissues. Functional assays suggested that overexpression of SERPINA3 significantly promoted cell proliferation, where migration and invasion of TNBC cells were accelerated. Knockdown of SERPINA3 had the opposite effects. These results causing by overexpression of SERPINA3 were also confirmed in non-TNBC cell lines. Overexpression of SERPINA3 remarkably enhanced the epithelial–mesenchymal transition (EMT) by upregulating the EMT markers and EZH2. In addition, the overexpression of SERPINA3 reduced the sensitivity of TNBC cells to cisplatin. Conclusion SERPINA3 can regulate the migration, invasion and EMT of TNBC cells and increased expression of SERPINA3 confers resistance to cisplatin in TNBC cells. We discern it is required for the regulation of BC progression and is a critical target for the clinical treatment of BC.

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