scholarly journals PSMB5 is associated with proliferation and drug resistance in triple-negative breast cancer

2017 ◽  
Vol 33 (1) ◽  
pp. 102-108 ◽  
Author(s):  
Wensong Wei ◽  
Yufeng Zou ◽  
Qihua Jiang ◽  
Zhibin Zhou ◽  
Haolong Ding ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Functional Module ◽  
Enrichment Analysis ◽  
Chemotherapeutic Agents ◽  
Gene Set Enrichment Analysis ◽  
Disease Stage ◽  
Cancer Subtypes

Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by advanced disease stage and poor prognosis. Moreover, due to the lack of therapeutic markers, TNBC patients can’t benefit fully from currently available targeted therapies. Methods: To fully understand the molecular basis of TNBC, we used gene set enrichment analysis (GSEA) to screen out the most altered functional module in TNBC, from publicly available microarray data and studied the association of the candidate gene with TNBC development. Results: We found that the proteasome was significantly activated in TNBC. As compared with other breast cancer subtypes and normal tissue, proteasome subunit beta 5 (PSMB5), the key regulator of proteasome function, was overexpressed in TNBC tissue and predictive of poor prognosis. Moreover, we also found that PSMB5 knockdown induced TNBC apoptosis and significantly enhanced cancer cell sensitivity to the chemotherapeutic agents bortezomib and paclitaxel. Conclusions: Our results suggest a potential role for PSMB5 as a biomarker and therapeutic target for TNBC.

scholarly journals Molecular stratification within triple-negative breast cancer subtypes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Dong-Yu Wang ◽  
Zhe Jiang ◽  
Yaacov Ben-David ◽  
James R. Woodgett ◽  
Eldad Zacksenhaus
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Cancer Subtypes ◽  
Molecular Stratification ◽  
Hazard Ratios ◽  
Programmed Cell Death 1 ◽  
Tgfβ Signalling ◽  
Survival Differences

AbstractTriple-negative breast cancer (TNBC) has been subdivided into six distinct subgroups: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), mesenchymal stem–like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR). We recently identified a subgroup of TNBC with loss of the tumor suppressor PTEN and five specific microRNAs that exhibits exceedingly poor clinical outcome and contains TP53 mutation, RB1 loss and high MYC and WNT signalling. Here, show that these PTEN-low/miRNA-low lesions cluster with BL1 TNBC. These tumors exhibited high RhoA signalling and were significantly stratified on the basis of PTEN-low/RhoA-signalling-high with hazard ratios (HRs) of 8.2 (P = 0.0009) and 4.87 (P = 0.033) in training and test cohorts, respectively. For BL2 TNBC, we identified AKT1 copy gain/high mRNA expression as surrogate for poor prognosis (HR = 3.9; P = 0.02 and HR = 6.1; P = 0.0032). In IM, programmed cell death 1 (PD1) was elevated and predictive of poor prognosis (HR = 5.3; P = 0.01 and HR = 3.5; P < 0.004). Additional alterations, albeit without prognostic power, characterized each subtype including high E2F2 and TGFβ signalling and CXCL8 expression in BL2, high IFNα and IFNγ signalling and CTLA4 expression in IM, and high EGFR signalling in MSL, and may be targeted for therapy. This study identified PTEN-low/RhoA-signalling-high, and high AKT1 and PD1 expression as potent prognostications for BL1, BL2 and IM subtypes with survival differences of over 14, 2.75 and 10.5 years, respectively. This intrinsic heterogeneity could be exploited to prioritize patients for precision medicine.

scholarly journals Management Options in Triple-Negative Breast Cancer

2011 ◽  
Vol 5 ◽  
pp. BCBCR.S6562 ◽  
Author(s):  
Christina A. Minami ◽  
Debra U. Chung ◽  
Helena R. Chang
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Brca1 Mutation ◽  
Chemotherapeutic Agents ◽  
Disease Entity ◽  
Management Options ◽  
Biological Specificity ◽  
Broad Overview

Notorious for its poor prognosis and aggressive nature, triple-negative breast cancer (TNBC) is a heterogeneous disease entity. The nature of its biological specificity, which is similar to basal-like cancers, tumors arising in BRCA1 mutation carriers, and claudin-low cancers, is currently being explored in hopes of finding the targets for novel biologics and chemotherapeutic agents. In this review, we aim to give a broad overview of the disease's nomenclature and epidemiology, as well as the basic mechanisms of emerging targeted therapies and their performance in clinical trials to date.

scholarly journals Immune Milieu and Genomic Alterations Set the Triple-Negative Breast Cancer Immunomodulatory Subtype Tumor Behavior

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6256
Author(s):  
Rubén Rodríguez-Bautista ◽  
Claudia H. Caro-Sánchez ◽  
Paula Cabrera-Galeana ◽  
Gerardo J. Alanis-Funes ◽  
Everardo Gutierrez-Millán ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune System ◽  
Dna Sequencing ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Patterns ◽  
Tumor Biology ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Genomic Alterations

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease. Seven subtypes have been described based on gene expression patterns. Herein, we characterized the tumor biology and clinical behavior of the immunomodulatory (IM) subtype. Methods: Formalin-fixed paraffin-embedded tumor samples from 68 high-risk (stage III-IV) TNBC patients were analyzed through microarrays, immunohistochemistry, and DNA sequencing. Results: The IM subtype was identified in 24% of TNBC tumor samples and characterized by a higher intratumoral (intT) and stromal (strml) infiltration of FOXP3+ TILs (Treg) compared with non-IM subtypes. Further, PD-L1+ (>1%) expression was significantly higher, as well as CTLA-4+ intT and strml expression in the IM subtype. Differential expression and gene set enrichment analysis identified biological processes associated with the immune system. Pathway analysis revealed enrichment of the β-catenin signaling pathway. The non-coding analysis led to seven Long Intergenic Non-Protein Coding RNAs (lincRNAs) (6 up-regulated and 1 down-regulated) that were associated with a favorable prognosis in the TNBC-IM subtype. The DNA sequencing highlighted two genes relevant to immune system responses: CTNNB1 (Catenin β-1) and IDH1. Conclusion: the IM subtype showed a distinct immune microenvironment, as well as subtype-specific genomic alterations. Characterizing TNBC at a molecular and transcriptomic level might guide immune-based therapy in this subgroup of patients.

The clinical impact of the expression of the cancer stem cell marker CD44v9 in early triple negative breast cancer (TNBC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12566-e12566
Author(s):  
Eriko Tokunaga ◽  
Wakako Tajiri ◽  
Katsumi Takizawa ◽  
Hideki Ijichi ◽  
Hiroki Ueo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Chemotherapeutic Agents ◽  
Clinical Impact ◽  
High Expression ◽  
Stem Cell Marker ◽  
Low Grade ◽  
The Poor

e12566 Background: The adhesion molecule CD44 is expressed in cancer stem-like cells (CSCs). CD44 variant 9 (CD44v9), a splicing variant of CD44, has emerged as a novel marker of cancer stemness. CD44v9 was reported to be associated with the resistance to chemotherapy in several malignancies. We recently reported that the high expression of CD44v9 is associated with the poor prognosis of the patients with triple negative breast cancer (TNBC), who received neoadjuvant chemotherapy (NAC). In this study, we investigated the clinical impact of the expression of CD44v9 in early TNBC who underwent surgery without NAC. Methods: Among 2257 primary breast cancer patients at clinical stage I-III who underwent surgery without NAC form 2002 to 2015, 201 patients with TNBC were included in this study. The expression of CD44v9 was analyzed immunohistochemistry (IHC). The associations between the CD44v9 expression and the clinicopathological characteristics and the prognosis were investigated. The tumors with the positive staining in more than two third of the cancer cells were regarded to be high expression of CD44v9. Results: CD44v9 high expression was observed in 62 cases (30.8%) and the low expression was in 139 cases (69.2%). Many of the CD44v9 high tumors were low grade than the tumors with low CD44v9. There were no significant associations between the expression levels of CD44v9 and the tumor size, lymph node metastasis and the pathological stage (pStage). There were no differences in the prognosis between the high and low CD44v9 expression in pStage I. However, in the patients with the tumors with pT1c or more (pT2, pT3) and the patients with pStage 2 and more, the high CD44v9 expression was significantly associated with the poor prognosis in terms of distant recurrence-free survival (DRFS) and overall survival (OS). In addition, high CD44v9 was associated with significantly shorter survival after recurrence. Many of these patients received various chemotherapy in the adjuvant setting and after recurrence. Therefore, CD44v9 high expression is considered to be associated with the poor prognosis due to the resistance to various chemotherapeutic agents. Conclusions: The prognosis of the TNBC patients with the high expression of CD44v9 is poor, which might be induced by the resistance to various chemotherapeutic agents. These results suggest that CD44v9 might be a novel therapeutic target for TNBC.

Current Update on Natural Agents Against Triple Negative Breast Cancer

2020 ◽  
pp. 91-113
Author(s):  
Prathibha Sivaprakasam ◽  
Sureshkumar Anandasadagopan ◽  
Tamilselvi Alagumuthu ◽  
Ashok Kumar Pandurangan
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Notch Pathway ◽  
Chemotherapeutic Agents ◽  
Current Evidence ◽  
Research Needs ◽  
Disease Entity ◽  
Natural Agents

Breast cancer (BC) is sub-categorized into several well-recognized subtypes including estrogen receptor (ER), progesterone receptor (PR), and HER2 triple-negative breast cancer (TNBC). It is a heterogeneous disease entity constituting about 15% of breast cancer cases worldwide. TNBC is associated with poor prognosis and lack of sustained response to conventional chemotherapeutic agents. Although no approved targeted therapy is available for TNBCs, molecular-profiling efforts have revealed promising molecular targets such as the Wnt/β-catenin, STAT3, VEGF, EGFR, polyadenosine ribose polymerase inhibitors (PARPi) and DNA repair pathway, androgen pathway, and NOTCH pathway. Moreover, more research needs to be performed in the area of TNBC aiming at dissecting potential pathways and identifying potential molecular signatures to develop new targeted biologic modifiers. Natural agents are the abundant chemical compounds available from diverse plants. The authors aimed to summarize the current evidence and discuss the natural agents that target TNBC using different pathways.

scholarly journals GBP5 Serves as a Potential Marker to Predict a Favorable Response in Triple-Negative Breast Cancer Patients Receiving a Taxane-Based Chemotherapy

2021 ◽  
Vol 11 (3) ◽  
pp. 197
Author(s):  
Shun-Wen Cheng ◽  
Po-Chih Chen ◽  
Tzong-Rong Ger ◽  
Hui-Wen Chiu ◽  
Yuan-Feng Lin
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Computational Simulation ◽  
Prognostic Significance ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Breast Cancer Patients ◽  
Potential Marker ◽  
Signaling Axis

Pre-operative (neoadjuvant) or post-operative (adjuvant) taxane-based chemotherapy is still commonly used to treat patients with triple-negative breast cancer (TNBC). However, there are still no effective biomarkers used to predict the responsiveness and efficacy of taxane-based chemotherapy in TNBC patients. Here we find that guanylate-binding protein 5 (GBP5), compared to other GBPs, exhibits the strongest prognostic significance in predicting TNBC recurrence and progression. Whereas GBP5 upregulation showed no prognostic significance in non-TNBC patients, a higher GBP5 level predicted a favorable recurrence and progression-free condition in the TNBC cohort. Moreover, we found that GBP5 expression negatively correlated with the 50% inhibitory concentration (IC50) of paclitaxel in a panel of TNBC cell lines. The gene knockdown of GBP5 increased the IC50 of paclitaxel in the tested TNBC cells. In TNBC patients receiving neoadjuvant or adjuvant chemotherapy, a higher GBP5 level strongly predicted a good responsiveness. Computational simulation by the Gene Set Enrichment Analysis program and cell-based assays demonstrated that GBP5 probably enhances the cytotoxic effectiveness of paclitaxel via activating the Akt/mTOR signaling axis and suppressing autophagy formation in TNBC cells. These findings suggest that GBP5 could be a good biomarker to predict a favorable outcome in TNBC patients who decide to receive a taxane-based neoadjuvant or adjuvant therapy.

scholarly journals Brachyury, a vaccine target, is overexpressed in triple-negative breast cancer

2016 ◽  
Vol 23 (10) ◽  
pp. 783-796 ◽  
Author(s):  
Duane H Hamilton ◽  
Mario Roselli ◽  
Patrizia Ferroni ◽  
Leopoldo Costarelli ◽  
Francesco Cavaliere ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Tumor Metastasis ◽  
Triple Negative ◽  
Strong Association ◽  
High Rate ◽  
Therapeutic Interventions ◽  
Primary Tumors ◽  
Cancer Subtypes

Patients diagnosed with triple-negative breast cancer (TNBC) have a high rate of tumor metastasis and a poor prognosis. The treatment option for these patients is currently chemotherapy, which results in very low response rates. Strategies that exploit the immune system for the treatment of cancer have now shown the ability to improve survival in several tumor types. Identifying potential targets for immune therapeutic interventions is an important step in developing novel treatments for TNBC. In this study,in silicoanalysis of publicly available datasets and immunohistochemical analysis of primary and metastatic tumor biopsies from TNBC patients were conducted to evaluate the expression of the transcription factor brachyury, which is a driver of tumor metastasis and resistance and a target for cancer vaccine approaches. Analysis of breast cancer datasets demonstrated a predominant expression of brachyury mRNA in TNBC and in basal vs luminal or HER2 molecular breast cancer subtypes. At the protein level, variable levels of brachyury expression were detected both in primary and metastatic TNBC lesions. A strong association was observed between nuclear brachyury protein expression and the stage of disease, with nuclear brachyury being more predominant in metastatic vs primary tumors. Survival analysis also demonstrated an association between high levels of brachyury in the primary tumor and poor prognosis. Two brachyury-targeting cancer vaccines are currently undergoing clinical evaluation; the data presented here provide rationale for using brachyury-targeting immunotherapy approaches for the treatment of TNBC.

scholarly journals Identification of FPR3 as a Unique Biomarker for Targeted Therapy in the Immune Microenvironment of Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jian Qi ◽  
Yu Liu ◽  
Jiliang Hu ◽  
Li Lu ◽  
Zhen Dou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Network Analysis ◽  
Poor Prognosis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Tumor Stages ◽  
Immune Score

Although research into immunotherapy is growing, its use in the treatment of breast cancer remains limited. Thus, identification and evaluation of prognostic biomarkers of tissue microenvironments will reveal new immune-based therapeutic strategies for breast cancer. Using an in silico bioinformatic approach, we investigated the tumor microenvironmental and genetic factors related to breast cancer. We calculated the Immune score, Stromal score, Estimate score, Tumor purity, TMB (Tumor mutation burden), and MATH (Mutant-allele tumor heterogeneity) of Breast cancer patients from the Cancer Genome Atlas (TCGA) using the ESTIMATE algorithm and Maftools. Significant correlations between Immune/Stromal scores with breast cancer subtypes and tumor stages were established. Importantly, we found that the Immune score, but not the Stromal score, was significantly related to the patient's prognosis. Weighted correlation network analysis (WGCNA) identified a pattern of gene function associated with Immune score, and that almost all of these genes (388 genes) are significantly upregulated in the higher Immune score group. Protein-protein interaction (PPI) network analysis revealed the enrichment of immune checkpoint genes, predicting a good prognosis for breast cancer. Among all the upregulated genes, FPR3, a G protein-coupled receptor essential for neutrophil activation, is the sole factor that predicts poor prognosis. Gene set enrichment analysis analysis showed FRP3 upregulation synergizes with the activation of many pathways involved in carcinogenesis. In summary, this study identified FPR3 as a key immune-related biomarker predicting a poor prognosis for breast cancer, revealing it as a promising intervention target for immunotherapy.

Identification of new therapeutic leads for triple negative breast cancer subtypes

Planta Medica ◽  
2015 ◽  
Vol 81 (11) ◽  
Author(s):  
AJ Robles ◽  
L Du ◽  
S Cai ◽  
RH Cichewicz ◽  
SL Mooberry
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Subtypes ◽  
Cancer Subtypes ◽  
Therapeutic Leads
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