Prognostic and Therapeutic Values of Autophagy-related Genes in Triple-negative Breast Cancer

Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with poor prognosis. Therefore, it is imperative to develop new prognostic or therapeutic biomarkers for TNBC. Objective: To explore the prognostic and therapeutic values of autophagy-related genes (ARGs) in TNBC. Methods: Overall, 157 TNBC patients’ data were obtained from The Cancer Genome Atlas database, and the ARGs were acquired from the Human Autophagy Database. Differentially expressed ARGs (DEGs) between tumor and normal tissues were identified and the prognostic ARGs were developed using R software. Kaplan–Meier survival curves and receiver operating characteristic (ROC) curves were both used to evaluate the accuracy of the signature. Patents about prognostic ARGs were reviewed through Worldwide Espacenet® and Patentscope®. Results: We obtained 28 DEGs and two prognostic ARGs (EIF4EBP1 and PARP1). The Kaplan–Meier survival curves showed that the survival rate of patients with low 2-ARG signature risk score was significantly higher than that of patients with high risk score (P=0.003). ROC at 5 years indicated that the signature had good prognostic accuracy (AUC=0.929). The signature was independent of T, N, M, and TNM stage (P<0.05). Patent review suggested that many mTOR inhibitors alone or in combination with another anticancer agent have been provided for treatment of many cancers and shown promising results. No drug patents about PARP1 overexpression were disclosed. Conclusion: We developed a 2-ARG signature (EIF4EBP1 and PARP1) which was an independent prognostic biomarker for TNBC. As EIF4EBP1 was upregulated in TNBC, mTOR inhibitors which blocked the mTOR/4EBP1/eIF4E pathway may be a promising therapeutic strategy for TNBC.

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The Functional Impact of Alternative Splicing on the Survival Prognosis of Triple-Negative Breast Cancer

Frontiers in Genetics ◽

10.3389/fgene.2020.604262 ◽

2021 ◽

Vol 11 ◽

Author(s):

Sijia Wu ◽

Jiachen Wang ◽

Xinchao Zhu ◽

Jacqueline Chyr ◽

Xiaobo Zhou ◽

...

Keyword(s):

Breast Cancer ◽

Risk Factor ◽

Alternative Splicing ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Roc Curves ◽

The Cancer Genome Atlas ◽

Survival Prognosis ◽

Kaplan Meier

PurposeTriple-negative breast cancer (TNBC) is a type of breast cancer (BC) showing a high recurrence ratio and a low survival probability, which requires novel actionable molecular targets. The involvement of alternative splicing (AS) in TNBC promoted us to study the potential roles of AS events in the survival prognosis of TNBC patients.MethodsA total of 150 TNBC patients from The Cancer Genome Atlas (TCGA) were involved in this work. To study the effects of AS in the recurrence-free survival (RFS) prognosis of TNBC, we performed the analyses as follows. First, univariate Cox regression model was applied to identify RFS-related AS events. Their host genes were analyzed by Metascape to discover the potential functions and involved pathways. Next, least absolute shrinkage and selection operator (LASSO) method was used to select the most informative RFS-related AS events to constitute an AS risk factor for RFS prognosis, which was evaluated by Kaplan–Meier (KM) and receiver operating characteristic (ROC) curves in all the data and also in different clinical subgroups. Furthermore, we analyzed the relationships between splicing factors (SFs) and these RFS-related AS events to seek the possibility that SFs regulated AS events to influence RFS. Then, we evaluated the potential of these RFS-related AS events in the overall survival (OS) prognosis from all the above aspects.ResultsWe identified a total of 546 RFS-related AS events, which were enriched in some splicing and TNBC-associated pathways. Among them, seven RFS-related events were integrated into a risk factor, exhibiting satisfactory RFS prognosis alone and even better performance when combined with clinical tumor–node–metastasis stages. Furthermore, the correlation analysis between SFs and the seven AS events revealed the hypotheses that SRPK3 might upregulate PCYT2_44231_AA to have an effect on RFS prognosis and that three other SFs may work together to downregulate FLAD1_7874_RI to influence RFS prognosis. In addition, the seven RFS-related AS events were validated to be promising in the OS prognosis of TNBC as well.ConclusionThe abnormal AS events regulated by SFs may act as a kind of biomarker for the survival prognosis of TNBC.

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Characterization of ceRNA network to reveal potential prognostic biomarkers in triple-negative breast cancer

PeerJ ◽

10.7717/peerj.7522 ◽

2019 ◽

Vol 7 ◽

pp. e7522 ◽

Cited By ~ 6

Author(s):

Xiang Song ◽

Chao Zhang ◽

Zhaoyun Liu ◽

Qi Liu ◽

Kewen He ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Quantitative Polymerase Chain Reaction ◽

The Cancer Genome Atlas ◽

Expression Level ◽

Cerna Network ◽

Kaplan Meier ◽

Cancer Genome Atlas ◽

Non Coding Rnas

Triple-negative breast cancer (TNBC) is a particular subtype of breast malignant tumor with poorer prognosis than other molecular subtypes. Previous studies have demonstrated that some abnormal expression of non-coding RNAs including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) were closely related to tumor cell proliferation, apoptosis, invasion, migration and drug sensitivity. However, the role of non-coding RNAs in the pathogenesis of TNBC is still unclear. In order to characterize the molecular mechanism of non-coding RNAs in TNBC, we downloaded RNA data and miRNA data from the cancer genome atlas database. We successfully identified 686 message RNAs (mRNAs), 26 miRNAs and 50 lncRNAs as key molecules for high risk of TNBC. Then, we hypothesized that the lncRNA–miRNA–mRNA regulatory axis positively correlates with TNBC and constructed a competitive endogenous RNA (ceRNA) network of TNBC. Our series of analyses has shown that five molecules (TERT, TRIML2, PHBP4, mir-1-3p, mir-133a-3p) were significantly associated with the prognosis of TNBC, and there is a prognostic ceRNA sub-network between those molecules. We mapped the Kaplan–Meier curve of RNA on the sub-network and also suggested that the expression level of the selected RNA is related to the survival rate of breast cancer. Reverse transcription-quantitative polymerase chain reaction showed that the expression level of TRIML2 in TNBC cells was higher than normal. In general, our findings have implications for predicting metastasis, predicting prognosis and discovering new therapeutic targets for TNBC.

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A novel three-long noncoding RNA risk score system for the prognostic prediction of triple-negative breast cancer

Biomarkers in Medicine ◽

10.2217/bmm-2020-0505 ◽

2021 ◽

Vol 15 (1) ◽

pp. 43-55

Author(s):

Chao Yuan ◽

Hongjun Yuan ◽

Li Chen ◽

Miaomiao Sheng ◽

Wenru Tang

Keyword(s):

Breast Cancer ◽

Risk Score ◽

Triple Negative Breast Cancer ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Triple Negative ◽

Cox Regression ◽

Characteristic Curve ◽

Gene Expression Omnibus ◽

Prognostic Prediction

Background: Triple-negative breast cancer (TNBC) is characterized by fast tumor increase, rapid recurrence and natural metastasis. We aimed to identify a genetic signature for predicting the prognosis of TNBC. Materials & methods: We conducted a weighted correlation network analysis of datasets from the Gene Expression Omnibus. Multivariate Cox regression was used to construct a risk score model. Results: The multi-factor risk scoring model was meaningfully associated with the prognosis of patients with TBNC. The predictive power of the model was demonstrated by the time-dependent receiver operating characteristic curve and Kaplan–Meier curve, and verified using a validation set. Conclusion: We established a long noncoding RNA-based model for the prognostic prediction of TNBC.

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The BIRC Family Genes Expression in Patients with Triple Negative Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22041820 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1820

Author(s):

Anna Makuch-Kocka ◽

Janusz Kocki ◽

Anna Brzozowska ◽

Jacek Bogucki ◽

Przemysław Kołodziej ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Clinical Data ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Lymphatic Vessels ◽

The Cancer Genome Atlas ◽

Expression Level ◽

Cancer Tissue ◽

Expression Levels

The BIRC (baculoviral IAP repeat-containing; BIRC) family genes encode for Inhibitor of Apoptosis (IAP) proteins. The dysregulation of the expression levels of the genes in question in cancer tissue as compared to normal tissue suggests that the apoptosis process in cancer cells was disturbed, which may be associated with the development and chemoresistance of triple negative breast cancer (TNBC). In our study, we determined the expression level of eight genes from the BIRC family using the Real-Time PCR method in patients with TNBC and compared the obtained results with clinical data. Additionally, using bioinformatics tools (Ualcan and The Breast Cancer Gene-Expression Miner v4.5 (bc-GenExMiner v4.5)), we compared our data with the data in the Cancer Genome Atlas (TCGA) database. We observed diverse expression pattern among the studied genes in breast cancer tissue. Comparing the expression level of the studied genes with the clinical data, we found that in patients diagnosed with breast cancer under the age of 50, the expression levels of all studied genes were higher compared to patients diagnosed after the age of 50. We observed that in patients with invasion of neoplastic cells into lymphatic vessels and fat tissue, the expression levels of BIRC family genes were lower compared to patients in whom these features were not noted. Statistically significant differences in gene expression were also noted in patients classified into three groups depending on the basis of the Scarff-Bloom and Richardson (SBR) Grading System.

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Actionable Gene Alterations in an Asian Population With Triple-Negative Breast Cancer

JCO Precision Oncology ◽

10.1200/po.17.00211 ◽

2018 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Masayuki Nagahashi ◽

YiWei Ling ◽

Tetsu Hayashida ◽

Yuko Kitagawa ◽

Manabu Futamura ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Ethnic Diversity ◽

Triple Negative ◽

Asian Population ◽

Japanese Patients ◽

The United States ◽

The Cancer Genome Atlas ◽

Cancer Genes ◽

Asian Patients

Purpose It has been suggested that the biologic characteristics of breast cancer may differ among different geographic or ethnic populations. Indeed, triple-negative breast cancer (TNBC), the most lethal breast cancer subgroup, has been reported to occur at a higher incidence in Japan than in the United States. However, most genomic studies of these tumors are from Western countries, and the genomic landscape of TNBC in an Asian population has not been thoroughly investigated. Here, we sought to elucidate the geographic and ethnic diversity of breast cancer by examining actionable driver alterations in TNBC tumors from Japanese patients and comparing them with The Cancer Genome Atlas (TCGA) database, which gathers data primarily from non-Asian patients. Materials and Methods We performed comprehensive genomic profiling, including an analysis of 435 known cancer genes, among Japanese patients with TNBC (n = 53) and compared the results with independent data obtained from TCGA (n = 123). Results Driver alterations were identified in 51 (96%) of 53 Japanese patients. Although the overall alteration spectrum among Japanese patients was similar to that of TCGA, we found significant differences in the frequencies of alterations in MYC and PTK2. We identified three patients (5.7%) with a high tumor mutational burden, although no microsatellite instability was observed in any of the Japanese patients. Importantly, pathway analysis revealed that 66.0% (35 of 53) of Japanese patients, as well as 66.7% (82 of 123) of TCGA cohort, had alterations in at least one actionable gene targetable by US Food and Drug Administration–approved drug. Conclusion Our study identified actionable driver alterations in Japanese patients with TNBC, revealing new opportunities for targeted therapies in Asian patients.

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Prognostic role of GPER/Ezrin in triple-negative breast cancer is associated with menopausal status

Endocrine Connections ◽

10.1530/ec-19-0164 ◽

2019 ◽

Vol 8 (6) ◽

pp. 661-671 ◽

Cited By ~ 6

Author(s):

Shuang Ye ◽

Yuanyuan Xu ◽

Jiehao Li ◽

Shuhui Zheng ◽

Peng Sun ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Menopausal Status ◽

Prognostic Significance ◽

Multivariable Analysis ◽

Survival Prognosis ◽

Kaplan Meier

The role of G protein-coupled estrogen receptor 1 (GPER) signaling, including promotion of Ezrin phosphorylation (which could be activated by estrogen), has not yet been clearly identified in triple-negative breast cancer (TNBC). This study aimed to evaluate the prognostic value of GPER and Ezrin in TNBC patients. Clinicopathologic features including age, menopausal status, tumor size, nuclear grade, lymph node metastasis, AJCC TNM stage, and ER, PR and HER-2 expression were evaluated from 249 TNBC cases. Immunohistochemical staining of GPER and Ezrin was performed on TNBC pathological sections. Kaplan–Meier analyses, as well as logistic regressive and Cox regression model tests were applied to evaluate the prognostic significance between different subgroups. Compared to the GPER-low group, the GPER-high group exhibited higher TNM staging (P = 0.021), more death (P < 0.001), relapse (P < 0.001) and distant events (P < 0.001). Kaplan–Meier analysis showed that GPER-high patients had a decreased OS (P < 0.001), PFS (P < 0.001), LRFS (P < 0.001) and DDFS (P < 0.001) than GPER-low patients. However, these differences in prognosis were not statistically significant in post-menopausal patients (OS, P = 0.8617; PFS, P = 0.1905; LRFS, P = 0.4378; DDFS, P = 0.2538). There was a significant positive correlation between GPER and Ezrin expression level (R = 0.508, P < 0.001) and the effect of Ezrin on survival prognosis corresponded with GPER. Moreover, a multivariable analysis confirmed that GPER and Ezrin level were both significantly associated with poor DDFS (HR: 0.346, 95% CI 0.182–0.658, P = 0.001; HR: 0.320, 95% CI 0.162–0.631, P = 0.001). Thus, overexpression of GPER and Ezrin may contribute to aggressive behavior and indicate unfavorable prognosis in TNBC; this may correspond to an individual’s estrogen levels.

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Identification of a Novel Gene Model-Based Homologous Recombination Deficiency Score to Improve Survival Prediction of TNBC.

10.21203/rs.3.rs-472194/v1 ◽

2021 ◽

Author(s):

Wenxiang Zhang ◽

Bolun Ai ◽

Xiangyi Kong ◽

Xiangyu Wang ◽

Jie Zhai ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Homologous Recombination ◽

Risk Score ◽

Cox Regression ◽

Roc Curves ◽

Cox Regression Analysis ◽

Homologous Recombination Deficiency ◽

Ajcc Stage ◽

Kaplan Meier

Abstract Background Triple-negative breast cancer (TNBC) is a specific histological type of breast cancer with a poor prognosis, early recurrence, which lacks durable chemotherapy responses and effective targeted therapies. We aimed to construct an accurate prognostic risk model based on homologous recombination deficiency (HRD) - gene expression profiles for improving prognosis prediction of TNBC. Methods Triple-negative breast cancer RNA sequencing data and sample clinical information were downloaded from the breast invasive carcinoma (BRCA) cohort in the Cancer Genome Atlas (TCGA) database. Combined with the HRD database, tumor samples were divided into two sets. We screened differentially expressed genes (DEGs) and then identified HRD-related prognostic genes using weighted gene co-expression network analysis (WGCNA) and Cox regression analysis. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were used to identifying key prognostic genes. Risk scores were calculated and compared with HRD score, Kaplan–Meier (KM) survival analysis were used to assess its prognostic power. GSE103091 dataset from GEO (Gene Expression Omnibus) database was used to validate the signature. Univariate and multivariate Cox regression were performed to independently verify the prognosis of the risk score. A nomogram was constructed and revealed by time-dependent ROC curves to guide clinical practice. Results We found that HRD tumor samples (HRD score > = 42) in TNBC patients were associated with poor overall survival (p = 0.027). We identified a total of 147 differential genes including 203 up-regulated and 213 down-regulated genes, among which 29 were prognosis-related genes. Through the LASSO method, 6 key prognostic genes ((MUCL1, IVL, FAM46C, CHI3L1, PRR15L, and CLEC3A) were selected and a 6-gene risk score was constructed. We found risk score was negatively associated with homologous recombination deficiency (HRD) scores (r = -0.22, p = 0.019). Compared with the low-risk group, Kaplan-Meier survival analysis shows that the high-risk group has an obvious poorer prognosis (P < 0.0001). Finally, we integrated the risk score model and clinical factors of TNBC (AJCC-stage, HRD score, T stage, and N stage) to construct a compound nomogram. Time-dependent ROC curves showed the risk score performed better in 1-, 3- and 5-year survival predictions compared with AJCC-stage. Conclusions Based on HRD gene expression data, our six HRD-related gene signature and nomogram could be practical and reliable tools for predicting OS in patients with TNBC.

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Nomogram Personalizes and Visualizes the Overall Survival of Patients with Triple-Negative Breast Cancer Based on the Immune Genome

BioMed Research International ◽

10.1155/2020/4029062 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Peipei Wang ◽

Yang Fu ◽

Yueyun Chen ◽

Qing Li ◽

Ye Hong ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

T Cells ◽

Risk Score ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Novel Therapy ◽

Immune Biomarkers ◽

Poorly Differentiated ◽

Immune Related Genes

Background. Triple-negative breast cancer (TNBC) is usually poorly differentiated, highly invasive, susceptible to distant metastasis, and less responsive to endocrine and targeted therapy. However, immunotherapy is a promising treatment for TNBC patients recently. Methods. The prognostic value of immune-related genes (IRGs) was explored by using RNA sequencing and microarray data of 123 and 107 TNBC patients from TCGA and GEO databases, respectively. Results. In TCGA database, GO and KEGG pathway analysis of 119 differential IRGs indicated that they actively participate in the interaction of cytokines and receptors. A nomogram model constructed by the prognosis-related CCL25, IL29, TDGF3, GPR44, and GREM2 in the IRGs could personalize and visualize the 1-, 2-, 3-, 4-, and 5-year overall survival (OS) of TNBC patients. Moreover, TNBC patients could be defined as low-risk ( risk score < 194 ) or high-risk ( risk score ≥ 194 ) cohorts based on the risk score derived from the nomogram model. The results could be validated by the GSE58812 dataset. Furthermore, the risk score was an independent risk factor for TNBC patients ( HR = 1.019 , 95% CI 1.012-1.027, p < 0.001 ) and was positively related to stage ( p = 0.017 ). Interestingly, the risk score could reflect the infiltration of B cells, CD4+ T cells, CD8+ T cells, dendritic cells, and neutrophils. Conclusion. These findings provided a reference for personalized OS prediction in TNBC patients and might be potential immune biomarkers for designing novel therapy.

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A Novel Platelet-Related Gene Signature for Predicting the Prognosis of Triple-Negative Breast Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.795600 ◽

2022 ◽

Vol 9 ◽

Author(s):

Jindong Xie ◽

Yutian Zou ◽

Feng Ye ◽

Wanzhen Zhao ◽

Xinhua Xie ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Risk Group ◽

Gene Signature ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Clinical Prognosis

Regarded as the most invasive subtype, triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) proteins. Platelets have recently been shown to be associated with metastasis of malignant tumors. Nevertheless, the status of platelet-related genes in TNBC and their correlation with patient prognosis remain unknown. In this study, the expression and variation levels of platelet-related genes were identified and patients with TNBC were divided into three subtypes. We collected cohorts from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. By applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, we constructed a seven-gene signature which classified the two cohorts of patients with TNBC into low- or high-risk groups. Patients in the high-risk group were more likely to have lower survival rates than those in the low-risk group. The risk score, incorporated with the clinical features, was confirmed as an independent factor for predicting the overall survival (OS) time. Functional enrichment analyses revealed the involvement of a variety of vital biological processes and classical cancer-related pathways that could be important to the ultimate prognosis of TNBC. We then built a nomogram that performed well. Moreover, we tested the model in other cohorts and obtained positive outcomes. In conclusion, platelet-related genes were closely related to TNBC, and this novel signature could serve as a tool for the assessment of clinical prognosis.

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High Expression of microRNA-223 Indicates a Good Prognosis in Triple-Negative Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.630432 ◽

2021 ◽

Vol 11 ◽

Author(s):

Li Chen ◽

Xiuzhi Zhu ◽

Boyue Han ◽

Lei Ji ◽

Ling Yao ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Molecular Subtype ◽

External Validation ◽

Disease Free Survival ◽

The Cancer Genome Atlas ◽

Locked Nucleic Acid ◽

Tnbc Subtype

PurposeMicroRNAs can influence many biological processes and have shown promise as cancer biomarkers. Few studies have focused on the expression of microRNA-223 (miR-223) and its precise role in breast cancer (BC). We aimed to examine the expression level of miR-223 and its prognostic value in BC.MethodsTissue microarray (TMA)-based miRNA detection in situ hybridization (ISH) with a locked nucleic acid (LNA) probe was used to detect miR-223 expression in 450 BC tissue samples. Overall survival (OS) and disease-free survival (DFS) were compared between two groups using the Kaplan-Meier method and Cox regression model.ResultsOS and DFS were prolonged in the high miR-223 expression group compared to the low miR-223 expression group (p < 0.0001 and p = 0.017, respectively), especially in patients with the triple-negative breast cancer (TNBC) subtype (p = 0.046 and p < 0.001, respectively). Univariate and multivariate Cox regression analyses revealed that TNM stage (p = 0.008), the molecular subtype (p = 0.049), and miR-223 (p < 0.001) were independently associated with OS and DFS. External validation was performed with the METABRIC and The Cancer Genome Atlas (TCGA) databases via online webtools and was consistent with the data described above.ConclusionsThis study provides evidence that high miR-223 expression at diagnosis is associated with improved DFS and OS for BC patients, especially those with the TNBC subtype. miR-223 is a valid and independent prognostic biomarker in BC.

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