A plasma protein derived TGFβ signature is a prognostic indicator in triple negative breast cancer.
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ABSTRACT:
SUBMITTER: Katayama H
PROVIDER: S-EPMC6445093 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A novel, highly selective biomarker is urgently needed to predict and monitor triple-negative breast cancer (TNBC) because targeting molecules are not currently available. Although associated with various malignant tumors, the role of toll-like receptor 5 (TLR5) in TNBC remains uncertain. We aimed to define the effects of TLR5 in TNBC to determine whether it could serve as a prognostic and monitoring indicator for TNBC. We established TNBC cell line 4T1 with low TLR5 expression (GFP tag; TLR5- 4T1) and with normal TLR5 expression (GFP tag; TLR5+ 4T1) using lentivirus-shRNA-TLR5 knockdown transfection and negative lentivirus transfection, respectively. Detected by western blot and qPCR, we found knockdown of TLR5 resulted in decreased expression of TLR5 and E-cadherin and increased expression of N-cadherin, vimentin, fibronectin, TRAF6, SOX2, and Twist1, which were related to EMT (epithelial-mesenchymal transition). In addition, downregulation of TLR5 increased the invasion and migration of 4T1 cells in vitro, which were investigated by CCK-8 and wound healing, as well as transwell assay and colony formation. Furthermore, the metastatic ability of TLR5- 4T1 cells to the lungs was also increased compared to TLR5+ 4T1 cells in vivo. To verify the effect of TLR5 as a monitor indicator, mice bearing TLR5+ and TLR5- 4T1 tumors injected with 125I-anti-TLR5 mAb or isotype 125I-IgG were assessed by whole body phosphor-autoradiography and fluorescence imaging in vivo. Phosphor-autoradiography of model mice revealed early tumors at 6 days after inoculation with TLR5+ 4T1, but not TLR5- 4T1 cells. Intratumoral accumulation of radioactivity positively correlated with TLR5 expression, and fluorescence imaging in vivo revealed both TLR5+ and TLR5- 4T1 tumors. Our results suggested that downregulation of TLR5 in TNBC increased tumor invasiveness and EMT expression via TRAF6 and SOX2 pathway and TLR5 could serve as a prognostic and monitoring indicator for TLR5-positive tumors.
| S-EPMC6920449 | biostudies-literature
Project description:BackgroundThe effect of extracellular microenvironment (hypoxia and pH) has been regarded as a key hallmark in cancer progression. The study aims to investigate the effects of carbonic anhydrase IX (CAIX), a key hypoxia-inducible marker, in triple-negative breast cancer (TNBC) in correlation with clinicopathological parameters and predicting survival outcomes.MethodsA total of 323 TNBC cases diagnosed at the Department of Anatomical Pathology, Singapore General Hospital from 2003 to 2013 were used. Immunohistochemical staining (IHC) was performed using CAIX antibody and digital mRNA quantification was performed using NanoString assays. CAIX membranous expression was correlated with clinicopathological parameters using Chi-squared test or Fisher's exact tests. Disease-free survival (DFS) and overall-survival (OS) were estimated using Kaplan-Meier analysis and compared between groups with the log-rank test.ResultsForty percent of TNBCs were observed to express CAIX protein and demonstrated significant association with larger tumour size (P = 0.002), higher histological grade (P < 0.001), and significantly worse disease-free survival (DFS) and overall survival (OS) (after adjustment: HR = 2.99, 95% CI = 1.78-5.02, P < 0.001 and HR = 2.56, 95% CI = 1.41-4.65, P = 0.002, respectively). Gene ontology enrichment analysis revealed six significantly enriched cellular functions (secretion, cellular component disassembly, regulation of protein complex assembly, glycolytic process, cellular macromolecular complex assembly, positive regulation of cellular component biogenesis) associated with genes differentially expressed (CAIX, SETX, WAS, HK2, DDIT4, TUBA4α, ARL1). Three genes (WAS, SETX and DDIT4) were related to DNA repair, indicating that DNA stability may be influenced by hypoxia in TNBC.ConclusionsOur results demonstrate that CAIX appears to be a significant hypoxia-inducible molecular marker and increased CAIX protein levels are independently associated with poor survival in TNBC. Identification of CAIX-linked seven gene-signature and its relationship with enriched cellular functions further support the implication and influence of hypoxia-mediated CAIX expression in TNBC tumour microenvironment.
| S-EPMC9164406 | biostudies-literature
Project description:BackgroundTriple-negative breast cancer (TNBC) is a highly aggressive type of cancer with few available treatment methods. The aim of the current study was to provide a prognostic autophagy-related gene (ARG) model to predict the outcomes for TNBC patients using bioinformatic analysis.MethodsmRNA expression data and its clinical information for TNBC samples obtained from The Cancer Genome Atlas (TCGA) and Metabric databases were extracted for bioinformatic analysis. Differentially expressed autophagy genes were identified using the Wilcoxon rank sum test in R software. ARGs were downloaded from the Human Autophagy Database. The Kaplan-Meier plotter was employed to determine the prognostic significance of the ARGs. The sample splitting method and Cox regression analysis were employed to establish the risk model and to demonstrate the association between the ARGs and the survival duration. The corresponding ARG-transcription factor interaction network was visualized using the Cytoscape software.ResultsA signature-based risk score model was established for eight genes (ITGA3, HSPA8, CTSD, ATG12, CLN3, ATG7, MAP1LC3C, and WIPI1) using the TCGA data and the model was validated with the GSE38959 and Metabric datasets, respectively. Patients with high risk scores had worse survival outcomes than those with low risk scores. Of note, amplification of ATG12 and reduction of WIPI were confirmed to be significantly correlated with the clinical stage of TNBC.ConclusionAn eight-gene autophagic signature model was developed in this study to predict the survival risk for TNBC. The genes identified in the study may favor the design of target agents for autophagy control in advanced TNBC.
| S-EPMC8840057 | biostudies-literature
Project description:We aimed to elucidate the landscape of tumor microenvironment (TME) in triple-negative breast cancer (TNBC). Cohorts from Gene Expression Omnibus database (N = 107) and METABRIC (N = 299) were used as the training set and validation set, respectively. TME was evaluated via single-sample gene set enrichment analysis, and unsupervised clustering was used for cluster identification. Consequently, TNBC was classified into two distinct TME clusters (Cluster 1 and Cluster 2) according to predefined immune-related terms. Cluster 1 was characterized by low immune infiltration with poor prognosis; whereas, Cluster 2 was characterized by high immune infiltration with better survival probability. Further, Cluster 1 had larger tumor volumes, while Cluster 2 had smaller tumor volumes. Finally, a TME signature for prognosis stratification in TNBC was developed and validated. In summary, we comprehensively evaluated the TME of TNBC and constructed a TME signature that correlated with prognosis. Our results provide new insights for the immunotherapy of TNBC.
| S-EPMC7950290 | biostudies-literature
Project description: Not available
| S-EPMC8764855 | biostudies-literature
Project description:Although triple negative breast cancers (TNBC) are the most aggressive subtype of breast cancer, they currently lack targeted therapies. Because this classification still includes a heterogeneous collection of tumors, new tools to classify TNBCs are urgently required in order to improve our prognostic capability for high risk patients and predict response to therapy. We previously defined a gene expression signature, RKIP Pathway Metastasis Signature (RPMS), based upon a metastasis-suppressive signaling pathway initiated by Raf Kinase Inhibitory Protein (RKIP). We have now generated a new BACH1 Pathway Metastasis gene signature (BPMS) that utilizes targets of the metastasis regulator BACH1. Specifically, we substituted experimentally validated target genes to generate a new BACH1 metagene, developed an approach to optimize patient tumor stratification, and reduced the number of signature genes to 30. The BPMS significantly and selectively stratified metastasis-free survival in basal-like and, in particular, TNBC patients. In addition, the BPMS further stratified patients identified as having a good or poor prognosis by other signatures including the Mammaprint® and Oncotype® clinical tests. The BPMS is thus complementary to existing signatures and is a prognostic tool for high risk ER-HER2- patients. We also demonstrate the potential clinical applicability of the BPMS as a single sample predictor. Together, these results reveal the potential of this pathway-based BPMS gene signature to identify high risk TNBC patients that can respond effectively to targeted therapy, and highlight BPMS genes as novel drug targets for therapeutic development.
| S-EPMC3859562 | biostudies-literature
Project description:PurposeImmune checkpoint blockade (ICB) therapy has transformed the treatment of triple-negative breast cancer (TNBC) in recent years. However, some TNBC patients with high programmed death-ligand 1 (PD-L1) expression levels develop immune checkpoint resistance. Hence, there is an urgent need to characterize the immunosuppressive tumor microenvironment and identify biomarkers to construct prognostic models of patient survival outcomes in order to understand biological mechanisms operating within the tumor microenvironment.Patients and methodsRNA sequence (RNA-seq) data from 303 TNBC samples were analyzed using an unsupervised cluster analysis approach to reveal distinctive cellular gene expression patterns within the TNBC tumor microenvironment (TME). A panel of T cell exhaustion signatures, immunosuppressive cell subtypes and clinical features were correlated with the immunotherapeutic response, as assessed according to gene expression patterns. The test dataset was then used to confirm the occurrence of immune depletion status and prognostic features and to formulate clinical treatment recommendations. Concurrently, a reliable risk prediction model and clinical treatment strategy were proposed based on TME immunosuppressive signature differences between TNBC patients with good versus poor survival status and other clinical prognostic factors.ResultsSignificantly enriched TNBC microenvironment T cell depletion signatures were detected in the analyzed RNA-seq data. A high proportion of certain immunosuppressive cell subtypes, 9 inhibitory checkpoints and enhanced anti-inflammatory cytokine expression profiles were noted in 21.4% of TNBC patients that led to the designation of this group of immunosuppressed patients as the immune depletion class (IDC). Although IDC group TNBC samples contained tumor-infiltrating lymphocytes present at high densities, IDC patient prognosis was poor. Notably, PD-L1 expression was relatively elevated in IDC patients that indicated their cancers were resistant to ICB treatment. Based on these findings, a set of gene expression signatures predicting IDC group PD-L1 resistance was identified then used to develop risk models for use in predicting clinical therapeutic outcomes.ConclusionA novel TNBC immunosuppressive tumor microenvironment subtype associated with strong PD-L1 expression and possible resistance to ICB treatment was identified. This comprehensive gene expression pattern may provide fresh insights into drug resistance mechanisms for use in optimizing immunotherapeutic approaches for TNBC patients.
| S-EPMC10292819 | biostudies-literature
Project description:There are no widely-accepted prognostic markers currently available to predict outcomes in patients with triple-negative breast cancer (TNBC), and no targeted therapies with confirmed benefit. We have used MALDI mass spectrometry imaging (MSI) of tryptic peptides to compare regions of cancer and benign tissue in 10 formalin-fixed, paraffin-embedded sections of TNBC tumors. Proteins were identified by reference to a peptide library constructed by LC-MALDI-MS/MS analyses of the same tissues. The prognostic significance of proteins that distinguished between cancer and benign regions was estimated by Kaplan-Meier analysis of their gene expression from public databases. Among peptides that distinguished between cancer and benign tissue in at least 3 tissues with a ROC area under the curve >0.7, 14 represented proteins identified from the reference library, including proteins not previously associated with breast cancer. Initial network analysis using the STRING database showed no obvious functional relationships except among collagen subunits COL1A1, COL1A2, and COL63A, but manual curation, including the addition of EGFR to the analysis, revealed a unique network connecting 10 of the 14 proteins. Kaplan-Meier survival analysis to examine the relationship between tumor expression of genes encoding the 14 proteins, and recurrence-free survival (RFS) in patients with basal-like TNBC showed that, compared to low expression, high expression of nine of the genes was associated with significantly worse RFS, most with hazard ratios >2. In contrast, in estrogen receptor-positive tumors, high expression of these genes showed only low, or no, association with worse RFS. These proteins are proposed as putative markers of RFS in TNBC, and some may also be considered as possible targets for future therapies.
2019-05-06 | PXD013397 | Pride
Project description:PurposeT-box transcription factor 21 (T-bet), which is the master regulator of effector T-cell activation, is derived by stimulation of T-cell receptors. In this study, we focused on T-bet and examined the function of activated T cells.MethodsThis study included 242 patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. The immunohistochemistry scoring for CD8 and T-bet expression on tumor-infiltrating lymphocytes (TILs) was defined as???30 per 6.25?×?10-3 mm2.ResultsOf the 242 TNBC cases, CD8 was positively expressed in 127 (52.5%) tumors, and T-bet was positively expressed in 67 (27.7%) tumors. T-bet expression was significantly correlated with CD8 expression (p?<?0.0001). Patients with T-bet+ tumors had longer overall survival (OS) compared with patients with T-bet- tumors (p?=?0.047). The combination of CD8+ and T-bet+ was associated with a better recurrence-free survival (RFS) and OS compared to CD8+/T-bet- tumors (p?=?0.037 and p?=?0.024, respectively). Adjuvant chemotherapy provided significantly greater benefit to patients with T-bet+ tumors (p?=?0.031 for RFS, p?=?0.0003 for OS). Multivariate analysis revealed that T-bet expression on TILs was an independent and positive prognostic indicator (HR?=?0.36, 95% confidence interval (CI) 0.12-0.94, p?=?0.037 for RFS, HR?=?0.30, 95% CI 0.07-0.95, p?=?0.039 for OS).ConclusionsOS was significantly improved for patients with high T-bet-expressing TILs in TNBC. Thus, T-bet may be a predictive indicator for survival and various immunotherapy strategies in TNBC.
| S-EPMC6586701 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) presents a major challenge in the clinic due to its lack of reliable prognostic markers and targeted therapies. Accumulating evidence strongly supports the notion that microRNAs (miRNAs) are involved in tumorigenesis and could serve as biomarkers for diagnostic purposes. To identify miRNAs that functionally suppress metastasis of TNBC, we employed a concerted approach with selecting miRNAs that display differential expression profiles from bioinformatic analyses of breast cancer patient databases and validating top candidates with functional assays using breast cancer cell lines and mouse models. We have found that miR-148a exhibits properties as a tumor suppressor as its expression is inversely correlated with the ability of both human and mouse breast cancer cells to colonize the lung in mouse xenograft tumor models. Mechanistically, miR-148a appears to suppress the extravasation process of cancer cells, likely by targeting two genes WNT1 and NRP1 in a cell non-autonomous manner. Importantly, lower expression of miR-148a is detected in higher-grade tumor samples and correlated with increased likelihood to develop metastases and poor prognosis in subsets of breast cancer patients, particularly those with TNBC. Thus, miR-148a is functionally defined as a suppressor of breast cancer metastasis and may serve as a prognostic biomarker for this disease.
| S-EPMC4991462 | biostudies-literature