Establishment and validation of an individualized macrophage-related gene signature to predict overall survival in patients with triple negative breast cancer

Background Recently, researchers have classified highly heterogeneous triple negative breast cancer (TNBC) into different subtypes from different perspectives and investigated the characteristics of different subtypes to pursue individualized treatment. With the increase of immunotherapy and its preliminary application in TNBC treatment, the value of immune-related strategies in the treatment of TNBC has been initially reflected. Based thereon, this study plans to classify and further explore TNBC from the perspective of immune cell infiltration. Method The fractions of immune cells of TNBC patients were assessed by six immune component analysis methods in The Cancer Genome Atlas (TCGA) database. Hub genes significantly related to poor prognosis were verified by weighted gene co-expression network analysis (WGCNA) analysis, Lasso analysis, and univariate KM analysis. Two cohorts of TNBC patients with complete prognosis information were collected for validation analysis. Finally, the Genomics of Drug Sensitivity in Cancer (GDSC) database was adopted to ascertain the sensitivity differences of different populations based on hub-gene grouping to different chemotherapy drugs. Results Five hub genes (CD79A, CXCL13, IGLL5, LHFPL2, and PLEKHF1) of the key co-expression gene module could divide TNBC patients into two groups (Cluster A and Cluster B) based on consistency cluster analysis. The patients with Cluster A were responsible for significantly worse prognosis than the patients with Cluster B (P = 0.023). In addition, another classification method, PCoA, and two other datasets (GSE103091 and GSE76124), were used to obtain consistent results with previous findings, which verified the stability of the classification method and dataset in this study. The grouping criteria based on the previous results were developed and the accuracy of the cut-off values was validated. A prognosis model of TNBC patients was then constructed based on the grouping results of five hub genes and N staging as prognostic factors. The results of ROC and decision curve analyses showed that this model had high prediction accuracy and patients could benefit therefrom. Finally, GDSC database analysis proved that patients in Cluster A were more sensitive to Vinorelbine. Separate analysis of the sensitivity of patients in Cluster A to Gemcitabine and Vinorelbine showed that the patients in Cluster A exhibited higher sensitivity to Vinorelbine. We hypothesized that these five genes were related to gemcitabine resistance and they could serve as biomarkers for clinical drug decision-making after anthracene resistance and taxane resistance in patients with advanced TNBC. Conclusion This study found five hub prognostic genes associated with macrophages, and a prognostic model was established to predict the survival of TNBC patients. Finally, these five genes were related to gemcitabine resistance in TNBC patients.

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Exploring specific prognostic biomarkers in triple-negative breast cancer

Cell Death and Disease ◽

10.1038/s41419-019-2043-x ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 6

Author(s):

Chang Bao ◽

Yunkun Lu ◽

Jishun Chen ◽

Danni Chen ◽

Weiyang Lou ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Target Genes ◽

Triple Negative ◽

Therapeutic Targets ◽

Good Prognosis ◽

The Cancer Genome Atlas ◽

Prognostic Biomarkers ◽

Luciferase Reporter ◽

Hub Genes

Abstract Lacking of both prognostic biomarkers and therapeutic targets, triple-negative breast cancer (TNBC) underscores pivotal needs to uncover novel biomarkers and viable therapies. MicroRNAs have broad biological functions in cancers and may serve as ideal biomarkers. In this study, by data mining of the Cancer Genome Atlas database, we screened out 4 differentially-expressed microRNAs (DEmiRNAs) between TNBC and normal samples: miR-135b-5p, miR-9-3p, miR-135b-3p and miR-455-5p. They were specially correlated with the prognosis of TNBC but not non-TNBC. The weighted correlation network analysis (WGCNA) for potential target genes of 3 good prognosis-related DEmiRNAs (miR-135b-5p, miR-9-3p, miR-135b-3p) identified 4 hub genes with highly positive correlation with TNBC subtype: FOXC1, BCL11A, FAM171A1 and RGMA. The targeting relationships between miR-9-3p and FOXC1/FAM171A1, miR-135b-3p and RGMA were validated by dual-luciferase reporter assays. Importantly, the regulatory functions of 4 DEmiRNAs and 3 verified target genes on cell proliferation and migration were explored in TNBC cell lines. In conclusion, we shed lights on these 4 DEmiRNAs (miR-135b-5p, miR-9-3p, miR-135b-3p, miR-455-5p) and 3 hub genes (FOXC1, FAM171A1, RGMA) as specific prognostic biomarkers and promising therapeutic targets for TNBC.

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Gene and lncRNA co-expression network analysis reveals novel ceRNA network for triple-negative breast cancer

Scientific Reports ◽

10.1038/s41598-019-51626-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 6

Author(s):

Kehao Le ◽

Hui Guo ◽

Qiulei Zhang ◽

Xiaojuan Huang ◽

Ming Xu ◽

...

Keyword(s):

Breast Cancer ◽

Network Analysis ◽

Triple Negative Breast Cancer ◽

Molecular Mechanisms ◽

Triple Negative ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Hub Genes ◽

Protein Coding ◽

Cerna Network

Abstract Breast cancer is the most frequently diagnosed malignancy among women, and triple-negative breast cancer (TNBC) is a highly aggressive subtype. Increasing evidence has shown that lncRNAs are involved in tumor growth, cell-cycle, and apoptosis through interactions with miRNAs or mRNAs. However, there is still limited data on ceRNAs involved in the molecular mechanisms underlying TNBC. In this study, we applied the weighted gene co-expression network analysis to the existing microarray mRNA and lncRNA expression data obtained from the breast tissues of TNBC patients to find the hub genes and lncRNAs involved in TNBC. Functional enrichment was performed on the module that correlated with Ki-67 status the most (Turquoise module). The hub genes in the Turquoise module were found to be associated with DNA repair, cell proliferation, and the p53 signaling pathway. We performed co-expression analysis of the protein-coding and lncRNA hub genes in the Turquoise module. Analysis of the RNA-seq data obtained from The Cancer Genome Atlas database revealed that the protein-coding genes and lncRNAs that were co-expressed were also differentially expressed in the TNBC tissues compared with the normal mammary tissues. On the basis of establishing the ceRNA network, two mRNAs (RAD51AP1 and TYMS) were found to be correlated with overall survival in TNBC. These results suggest that TNBC-specific mRNA and lncRNAs may participate in a complex ceRNA network, which represents a potential therapeutic target for the treatment 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 and Therapeutic Values of Autophagy-related Genes in Triple-negative Breast Cancer

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892816666211130170149 ◽

2021 ◽

Vol 16 ◽

Author(s):

Minling Liu ◽

Lei Li ◽

Shan Huang ◽

Xiaofen Pan ◽

Huiru Dai ◽

...

Keyword(s):

Breast Cancer ◽

Risk Score ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Mtor Inhibitors ◽

Roc Curves ◽

The Cancer Genome Atlas ◽

Survival Curves ◽

Prognostic Accuracy ◽

Kaplan Meier

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 overview of modern approaches in treatment of triple negative breast cancer

Research n Practical Medicine Journal ◽

10.17709/2409-2231-2020-7-1-6 ◽

2020 ◽

Vol 7 (1) ◽

pp. 55-65

Author(s):

A. A. Kharitonova ◽

I. A. Smirnova ◽

M. V. Kiseleva

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Parp Inhibitors ◽

Morphological Response ◽

Chemotherapy Drugs ◽

Treatment Regimens ◽

Dose Dense ◽

Platinum Preparations ◽

Aggressive Subtype

By far the most aggressive subtype of breast cancer is triple negative cancer. The purpose of this review is to analyze current ideas about the pathogenesis, clinical characteristics of different subtypes of triple negative breast cancer, the nature of its metastasis, mechanisms of chemoresistance. The review presents the results of modern regimens of drug therapy of triple negative breast cancer according to the publications of domestic and foreign oncologists. On the basis of various clinical studies, the effectiveness of the use of anthracyclines, taxanes in the dose-dense regime, platinum preparations and other chemotherapy drugs for the treatment of triple-negative cancer has been shown. The presented treatment regimens allow to achieve a complete morphological response in 85% of patients, to increase the rates of relapse-free and overall survival, comparable with other subtypes of breast cancer. The review highlights the possibilities of modern targeted drugs-PARP inhibitors, chk1 inhibitors UCN‑01, immunotherapy possibilities for the treatment of this aggressive subtype of breast cancer.

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Chemotherapy drugs derived nanoparticles encapsulating mRNA encoding tumor suppressor proteins to treat triple-negative breast cancer

Nano Research ◽

10.1007/s12274-019-2308-9 ◽

2019 ◽

Vol 12 (4) ◽

pp. 855-861 ◽

Cited By ~ 7

Author(s):

Chengxiang Zhang ◽

Xinfu Zhang ◽

Weiyu Zhao ◽

Chunxi Zeng ◽

Wenqing Li ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Chemotherapy Drugs ◽

Tumor Suppressor Proteins

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Loss of miR‑873 contributes to gemcitabine resistance in triple‑negative breast cancer via targeting ZEB1

Oncology Letters ◽

10.3892/ol.2019.10697 ◽

2019 ◽

Cited By ~ 5

Author(s):

Gangyue Wang ◽

Yi Dong ◽

Heng Liu ◽

Nan Ji ◽

Jilei Cao ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Gemcitabine Resistance

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Piperlongumine Induces Apoptosis and Synergizes with Doxorubicin by Inhibiting the JAK2-STAT3 Pathway in Triple-Negative Breast Cancer

Molecules ◽

10.3390/molecules24122338 ◽

2019 ◽

Vol 24 (12) ◽

pp. 2338 ◽

Cited By ~ 11

Author(s):

Di Chen ◽

Yangmin Ma ◽

Peiqi Li ◽

Meng Liu ◽

Yuan Fang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Xenograft Model ◽

Tumor Xenograft ◽

Stat3 Pathway ◽

Suppression Effect ◽

Chemotherapy Drugs ◽

Induced Apoptosis

Triple-negative breast cancer (TNBC) lacks major effective target molecules and chemotherapy remains the current main treatment. However, traditional chemotherapy drugs, such as doxorubicin (DOX), cause serious side effects and have a poor prognosis. Piperlongumine (PL), a natural alkaloid, has showed selective anticancer effects and is expected to become a new strategy against TNBC. In our research, cell viability, colony formation, flow cytometry, Western blot, and tumor xenograft model assays were established to evaluate the suppression effect of PL and DOX alone and in combination. Data showed that PL could effectively inhibit cell growth and induce apoptosis in two TNBC cell lines. We also demonstrated for the first time that the combination treatment of PL and DOX synergistically inhibited cell growth and induced apoptosis in TNBC cells. The suppression of STAT3 activation was indicated to be a mechanism of the anticancer effect. Moreover, the effectiveness of this combination was confirmed in a tumor xenograft model. These results revealed that inhibition of the JAK2-STAT3 pathway was a key anticancer mechanism when treated with PL alone or combined with DOX, suggesting that the combination of PL and chemotherapy drugs may be a potential strategy for the clinical treatment of TNBC.

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