scholarly journals Drivers and suppressors of triple-negative breast cancer

2021 ◽  
Vol 118 (33) ◽  
pp. e2104162118
Author(s):  
Wanfu Wu ◽  
Margaret Warner ◽  
Li Wang ◽  
Wei-Wei He ◽  
Ruipeng Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Acid Metabolite ◽  
Fatty Acid Metabolite ◽  
Unexpected Findings ◽  
Cytochrome P450 Family ◽  
Formalin Fixed

To identify regulators of triple-negative breast cancer (TNBC), gene expression profiles of malignant parts of TNBC (mTNBC) and normal adjacent (nadj) parts of the same breasts have been compared. We are interested in the roles of estrogen receptor β (ERβ) and the cytochrome P450 family (CYPs) as drivers of TNBC. We examined by RNA sequencing the mTNBC and nadj parts of five women. We found more than a fivefold elevation in mTNBC of genes already known to be expressed in TNBC: BIRC5/survivin, Wnt-10A and -7B, matrix metalloproteinases (MMPs), chemokines, anterior gradient proteins, and lysophosphatidic acid receptor and the known basal characteristics of TNBC, sox10, ROPN1B, and Col9a3. There were two unexpected findings: 1) a strong induction of CYPs involved in activation of fatty acids (CYP4), and in inactivation of calcitriol (CYP24A1) and retinoic acid (CYP26A1); and 2) a marked down-regulation of FOS, FRA1, and JUN, known tethering partners of ERβ. ERβ is expressed in 20 to 30% of TNBCs and is being evaluated as a target for treating TNBC. We used ERβ+ TNBC patient-derived xenografts in mice and found that the ERβ agonist LY500703 had no effect on growth or proliferation. Expression of CYPs was confirmed by immunohistochemistry in formalin-fixed and paraffin-embedded (FFPE) TNBC. In TNBC cell lines, the CYP4Z1-catalyzed fatty acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) increased proliferation, while calcitriol decreased proliferation but only after inhibition of CYP24A1. We conclude that CYP-mediated pathways can be drivers of TNBC but that ERβ is unlikely to be a tumor suppressor because the absence of its main tethering partners renders ERβ functionless on genes involved in proliferation and inflammation.

Epigenetic Reprogramming and Landscape of Transcriptomic Interactions: Impending Therapeutic Interference of Triple-Negative Breast Cancer in Molecular Medicine

2021 ◽  
Vol 21 ◽  
Author(s):  
Suman Kumar Ray ◽  
Sukhes Mukherjee
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Treatment Decision ◽  
Copy Number Variations ◽  
Molecular Medicine ◽  
Breast Cancers ◽  
Breast Carcinogenesis

: The mechanisms governing the development and progression of cancers are believed to be the consequence of hereditary deformities and epigenetic modifications. Accordingly, epigenetics has become an incredible and progressively explored field of research to discover better prevention and therapy for neoplasia, especially triple-negative breast cancer (TNBC). It represents 15–20% of all invasive breast cancers and will, in general, have bellicose histological highlights and poor clinical outcomes. In the early phases of triple-negative breast carcinogenesis, epigenetic deregulation modifies chromatin structure and influences the plasticity of cells. It up-keeps the oncogenic reprogramming of malignant progenitor cells with the acquisition of unrestrained selfrenewal capacities. Genomic impulsiveness in TNBC prompts mutations, copy number variations, as well as genetic rearrangements, while epigenetic remodeling includes an amendment by DNA methylation, histone modification, and noncoding RNAs of gene expression profiles. It is currently evident that epigenetic mechanisms assume a significant part in the pathogenesis, maintenance, and therapeutic resistance of TNBC. Although TNBC is a heterogeneous malaise that is perplexing to describe and treat, the ongoing explosion of genetic and epigenetic research will help to expand these endeavors. Latest developments in transcriptome analysis have reformed our understanding of human diseases, including TNBC at the molecular medicine level. It is appealing to envision transcriptomic biomarkers to comprehend tumor behavior more readily regarding its cellular microenvironment. Understanding these essential biomarkers and molecular changes will propel our capability to treat TNBC adequately. This review will depict the different aspects of epigenetics and the landscape of transcriptomics in triple-negative breast carcinogenesis and their impending application for diagnosis, prognosis, and treatment decision with the view of molecular medicine.

scholarly journals Decoding Immune Heterogeneity of Triple Negative Breast Cancer and Its Association with Systemic Inflammation

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 911 ◽  
Author(s):  
Romero-Cordoba ◽  
Meneghini ◽  
Sant ◽  
Iorio ◽  
Sfondrini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Systemic Inflammation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cytolytic Activity ◽  
Local Composition ◽  
Immune Infiltrate

Triple negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options. New opportunities are emerging from current comprehensive characterization of tumor immune infiltration and fitness. Therefore, effectiveness of current chemotherapies and novel immunotherapies are partially dictated by host inflammatory and immune profiles. However, further progress in breast cancer immuno-oncology is required to reach a detailed awareness of the immune infiltrate landscape and to determine additional reliable and easily detectable biomarkers. In this study, by analyzing gene expression profiles of 54 TNBC cases we identified three TNBC clusters displaying unique immune features. Deep molecular characterization of immune cells cytolytic-activity and tumor-inflammation status reveled variability in the local composition of the immune infiltrate in the TNBC clusters, reconciled by tumor-infiltrating lymphocytes counts. Platelet-to-lymphocyte ratio (PLR), a blood systemic parameter of inflammation evaluated using pre-surgical blood test data, resulted negatively correlated with local tumoral cytolytic activity and T cell–inflamed microenvironment, whereas tumor aggressiveness score signature positively correlated with PLR values. These data highlighted that systemic inflammation parameters may represent reliable and informative markers of the local immune tumor microenvironment in TNBC patients and could be exploited to decipher tumor infiltrate properties and consequently to select the most appropriate therapies.

scholarly journals Identification of TENM4 as a Novel Cancer Stem Cell-Associated Molecule and Potential Target in Triple Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 894 ◽  
Author(s):  
Roberto Ruiu ◽  
Giuseppina Barutello ◽  
Maddalena Arigoni ◽  
Federica Riccardo ◽  
Laura Conti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Gene Expression Profiles ◽  
Normal Breast ◽  
Metastatic Progression ◽  
Cancer Subtypes ◽  
Associated Proteins

Triple-negative breast cancer (TNBC) is insensitive to endocrine and Her2-directed therapies, making the development of TNBC-targeted therapies an unmet medical need. Since patients with TNBC frequently show a quicker relapse and metastatic progression compared to other breast cancer subtypes, we hypothesized that cancer stem cells (CSC) could have a role in TNBC. To identify putative TNBC CSC-associated targets, we compared the gene expression profiles of CSC-enriched tumorspheres and their parental cells grown as monolayer. Among the up-regulated genes coding for cell membrane-associated proteins, we selected Teneurin 4 (TENM4), involved in cell differentiation and deregulated in tumors of different histotypes, as the object for this study. Meta-analysis of breast cancer datasets shows that TENM4 mRNA is up-regulated in invasive carcinoma specimens compared to normal breast and that high expression of TENM4 correlates with a shorter relapse-free survival in TNBC patients. TENM4 silencing in mammary cancer cells significantly impaired tumorsphere-forming ability, migratory capacity and Focal Adhesion Kinase (FAK) phosphorylation. Moreover, we found higher levels of TENM4 in plasma from tumor-bearing mice and TNBC patients compared to the healthy controls. Overall, our results indicate that TENM4 may act as a novel biomarker and target for the treatment of TNBC.

scholarly journals Analysis of gene expression patterns in triple negative breast cancer: MERTK and WHSC1L1.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Black Women ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Primary Tumors

Triple negative breast cancer (TNBC) shares overlap with the basal molecular subtype of breast cancer and is more frequently diagnosed in African-American (black) women for reasons not understood (1,2). To understand genes whose expression may be of pertinence to the development or progression of triple negative breast cancer, we mined published microarray data (3,4) comparing global gene expression profiles of TNBC histology groups, identifying genes whose expression changed the least between among TNBCs, suggesting that these genes may be important for TNBC biology. We identified the MER proto-oncogene tyrosine kinase MERTK and the Wolf-Hirschhorn syndrome candidate 1-like 1 WHSC1L1 among the genes whose expression differed the least when comparing TNBC cases and subtypes. In another dataset, MERTK and WHSCL1 were found to be differentially expressed in TNBC when comparing primary tumors of the breast to normal breast tissue. Kaplan-Meier survival analysis revealed that expression levels of MERTK and WHSCL1 correlated with survival outcomes in human breast cancer, and that this correlation differed based on race of the patient. MERTK and WHSCL1 may be of relevance in understanding the etiology or progression of triple negative breast cancer.

scholarly journals Gene Expression Profiles Induced by High-dose Ionizing Radiation in MDA-MB-231 Triple-negative Breast Cancer Cell Line

2019 ◽  
Vol 16 (4) ◽  
pp. 257-266 ◽  
Author(s):  
VALENTINA BRAVATÀ ◽  
FRANCESCO PAOLO CAMMARATA ◽  
LUIGI MINAFRA ◽  
ROSA MUSSO ◽  
GAIA PUCCI ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Ionizing Radiation ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cell Line ◽  
Triple Negative ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cancer Cell Line ◽  
High Dose

Identification of CCNB2 expression in triple-negative breast cancer based on bioinformatics results

2021 ◽  
Author(s):  
jintao cao ◽  
SHUAI SUN ◽  
RAN LI ◽  
RUI MIN ◽  
XINGYU FAN ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Triple Negative Breast Cancer ◽  
Protein Complex ◽  
Triple Negative ◽  
Expression Profiles ◽  
Pathway Enrichment Analysis ◽  
Analysis Tool ◽  
The Core ◽  
Core Genes

Abstract Background The current epidemiology shows that the incidence of breast cancer is increasing year by year and tends to be younger. Triple-negative breast cancer is the most malignant of breast cancer subtypes. The application of bioinformatics in tumor research is becoming more and more extensive. This study provided research ideas and basis for exploring the potential targets of gene therapy for triple-negative breast cancer (TNBC). Methods We analyzed three gene expression profiles (GSE64790、GSE62931、GSE38959) selected from the Gene Expression Omnibus (GEO) database. The GEO2R online analysis tool was used to screen for differentially expressed genes (DEGs) between TNBC and normal tissues. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were applied to identify the pathways and functional annotation of DEGs. Protein–protein interaction network of these DEGs were visualized by the Metascape gene-list analysis tool so that we could find the protein complex containing the core genes. Subsequently, we investigated the transcriptional data of the core genes in patients with breast cancer from the Oncomine database. Moreover, the online Kaplan–Meier plotter survival analysis tool was used to evaluate the prognostic value of core genes expression in TNBC patients. Finally, immunohistochemistry (IHC) was used to evaluated the expression level and subcellular localization of CCNB2 on TNBC tissues. Results A total of 66 DEGs were identified, including 33 up-regulated genes and 33 down-regulated genes. Among them, a potential protein complex containing five core genes was screened out. The high expression of these core genes was correlated to the poor prognosis of patients suffering breast cancer, especially the overexpression of CCNB2. CCNB2 protein positively expressed in the cytoplasm, and its expression in triple-negative breast cancer tissues was significantly higher than that in adjacent tissues. Conclusions CCNB2 may play a crucial role in the development of TNBC and has the potential as a prognostic biomarker of TNBC.

scholarly journals Immunohistochemical analysis of CD155 expression in triple-negative breast cancer patients

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253176
Author(s):  
Katsuhiro Yoshikawa ◽  
Mitsuaki Ishida ◽  
Hirotsugu Yanai ◽  
Koji Tsuta ◽  
Mitsugu Sekimoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Profiles ◽  
Histological Grade ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Antitumor Immunotherapy

Introduction CD155 is an immune checkpoint protein. Its overexpression is an indicator of poor prognosis in some types of cancer. However, the significance of CD155 expression in patients with triple-negative breast cancer, and the relationship between CD155 and programmed death-ligand 1 (PD-L1) expression, have not yet been analyzed in detail. Methods Using immunohistochemical staining and tissue microarrays, we analyzed the expression profiles of CD155 and PD-L1 in 61 patients with triple-negative breast cancer. Relapse-free survival and overall survival rates were compared according to CD155 expression. The correlation between CD155 expression and clinicopathological factors, including PD-L1 expression (using SP142 and 73–10 assays), was also examined. Results CD155 expression was noted in 25 patients (41.0%) in this cohort. CD155 expression did not correlate with pathological stage, histological grade, Ki-67 labeling index, or stromal tumor-infiltrating lymphocytes. Only PD-L1 expression in tumor cells by SP142 assay significantly correlated with CD155 expression (p = 0.035); however, PD-L1 expression in tumor cells by 73–10 assay did not show a correlation (p = 0.115). Using the 73–10 assay, 59% of patients showed CD155 and/or PD-L1 expression in tumor cells. Moreover, using the SP142 assay, 63.3% of patients showed CD155 and/or PD-L1 expression in immune cells. CD155 expression did not correlate with either relapse-free survival or overall survival (p = 0.485 and 0.843, respectively). Conclusions CD155 may be a novel target for antitumor immunotherapy. The results of this study indicate that CD155 may expand the pool of candidates with triple-negative breast cancer who could benefit from antitumor immunotherapy.

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