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

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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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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An 8-lncRNA signature predicts the survival of triple-negative breast cancer patients without germline BRCA1/2 mutation

Medical Research ◽

10.6913/mrhk.202109_3(3).0003 ◽

2021 ◽

Vol 3 (3) ◽

pp. 15-32

Author(s):

Minling LIU ◽

Wei DAI ◽

Mengyuan ZHU ◽

Xueying LI ◽

Min WEI ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

The Cancer Genome Atlas ◽

Risk Scores ◽

Training Cohort ◽

Cox Regression Analysis ◽

Platinum Based Chemotherapy

Purpose: TNBC with germline BRCA1/2 mutation (gBRCAm) have higher sensitivity to DNA damaging agents including platinum-based chemotherapy and PARP inhibitors. But the treatment of TNBC without gBRCAm remains challenging. This study aimed to develop a long non-coding RNA (lncRNA) signature of TNBC patients without gBRCAm to improve risk stratification and optimize individualized treatment. Methods: 98 TNBC patients without gBRCAm were acquired from The Cancer Genome Atlas database. The univariable Cox regression analysis and LASSO Cox regression model were applied to establish an lncRNA signature in the training cohort. Then Kaplan–Meier survival curve and time-dependent ROC curve were used to validate the prognostic ability of the signature. The qPCR assay was performed to confirm the expressions and clinicopathological correlations of two potential lncRNAs HAGLROS and TONSL-AS1 in 30 paired clinical triple-negative breast cancer samples without gBRCAm. Results: We developed an 8-lncRNA signature in the training cohort including HAGLROS, AL139002.1, AL391244.2, AP000696.1, AL391056.1, AL513304.1, TONSL-AS1 and AL031008.1. Patients with higher risk scores showed significantly worse overall survival compared to those with lower risk scores (P=0.00018 and P =0.0068 respectively). 30 paired specimens of TNBC without gBRCAm in our center showed that two potential lncRNAs HAGLROS and TONSL-AS1 were found frequently overexpressed, and significantly associated with tumor grade and invasion. Conclusion: We constructed a novel 8-lncRNA signature which significantly associated with the overall survival of TNBC patients without gBRCAm. Among those 8 lncRNAs, HAGLROS and TONSL-AS1 may be potential therapeutic targets which function needed further exploration.

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Kallikrein-related peptidases in triple negative breast cancer: prognostic value of quantitatively assessed KLK8, KLK10 and KLK11 mRNA expression

10.21203/rs.3.rs-365110/v1 ◽

2021 ◽

Author(s):

Yueyang Liu ◽

Sarah Preis ◽

Geng Xiaocong ◽

Weiwei Gong ◽

Marion Kiechle ◽

...

Keyword(s):

Breast Cancer ◽

Mrna Expression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Prognostic Biomarker ◽

Disease Free Survival ◽

Mrna Levels ◽

Expression Levels ◽

Mrna Expression Levels

Abstract Background. Triple-negative breast cancer (TNBC) is a breast cancer subtype with poor prognosis and limited targeted therapy options. Multiple KLKs have been described to play key roles in carcinogenesis and metastasis of breast cancer. Purpose. In the present study, the clinical significance of KLK8, KLK10, and KLK11 mRNA expression in tumor tissue of TNBC patients was investigated. Methods. The mRNA expression levels of KLK8, 10, and 11 were quantified by quantitative PCR and their prognostic values were analyzed in a large, well-characterized TNBC cohort (n = 123). Results. Significantly positive correlations were observed between all three KLK mRNA levels indicating coordinate expression of these proteases in TNBC. In univariate analyses, both elevated KLK8, KLK10 as well as all combinations of the three factors (KLK8 + KLK10, KLK8 + KLK11, KLK10 + KLK11, KLK8 + KLK10 + KLK11) were significantly associated with shortened disease-free survival (DFS), while high mRNA levels of KLK11, as well as KLK10 + KLK11 were significantly associated with shortened overall survival (OS). In multivariate Cox regression analyses, KLK10 and all combined factors remained unfavorable independent predictive markers for DFS, while high KLK11 mRNA expression represented an unfavorable independent predictor for OS. Conclusions. Increased KLK8, KLK10, and KLK11 mRNA expression levels are associated with unfavorable prognosis in triple-negative breast cancer. The combination of KLK8 + KLK10 + KLK11 may represent a stronger prognostic biomarker for DFS than KLK8, KLK10, KLK11 alone, or other combinations thereof, whereas KLK11 mRNA expression is an independent prognostic biomarker for OS in TNBC patients.

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An Immunohistochemical Panel of Three SUMO Genes Predicts Outcomes of Patients With Triple-negative Breast Cancer

10.21203/rs.3.rs-109613/v1 ◽

2020 ◽

Author(s):

Yuxiang Lin ◽

Qingshui Wang ◽

Han Xiao ◽

Zhiwei Chen ◽

Meichen Jiang ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Disease Free Survival ◽

Chemotherapy Response ◽

Patient Counseling ◽

Predictive Tool ◽

Post Translational Modifications ◽

Response To Chemotherapy

Abstract Background: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease. Developing new candidate biomarkers for chemotherapy response and possible therapeutic targets has become an urgent clinical need. Small ubiquitin-like modifier (SUMOs) mediate post-translational modifications (SUMOylation) that target multiple proteins was involved in many biological processes. The role of SUMOylation in TNBC remains to be elucidated.Method: The expression of SUMO1/2/3 were analyzed using TCGA and GEO databases (N=412). We also evaluated the SUMO1/2/3 protein expression in 212 local TNBC patients using immunohistochemical (IHC) staining. We then built a classifier with the LASSO Cox regression model based on associations between the expression of SUMO1/2/3 proteins and the disease-free survival (DFS) of TNBC patients. Results: Elevated SUMO1/2/3 levels were indicated to be associated with a poorer overall survival (OS) and DFS for TNBC patients. Using the LASSO model, we built a classifier based on the IHC scores of SUMO1/2/3 proteins and named it ‘SB classifier’. Patients with the SB classifier defined high score were found to have an unfavorable response to chemotherapy (HR 4.04, 2.14-7.63; p<0.0001). We then developed a nomogram to predict which patients might benefit from chemotherapy. Finally, our analysis provides insights on possible mechanisms that MYC activation causes the activation of SUMOylation. Conclusion: We constructed a reliable prognostic and predictive tool for TNBC patients treated with chemotherapy. It may facilitate patient counseling and individualize management of TNBC patients. Meanwhile, our results suggested that the activation of SUMOylation pathway in TNBC may be induced by MYC signaling.

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High expression of NR1D1 is associated with good prognosis in triple-negative breast cancer patients treated with chemotherapy

Breast Cancer Research ◽

10.1186/s13058-019-1197-x ◽

2019 ◽

Vol 21 (1) ◽

Cited By ~ 2

Author(s):

Hyelin Na ◽

Jinil Han ◽

Na-Lee Ka ◽

Min-Ho Lee ◽

Yoon-La Choi ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Nuclear Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Molecular Subtype ◽

Histological Grade ◽

Disease Free Survival ◽

Rank Test ◽

Breast Cancer Patients

Abstract Background Nuclear receptor subfamily 1, group D, member 1 (NR1D1) is a ligand-regulated nuclear receptor and transcriptional factor. Although recent studies have implicated NR1D1 as a regulator of DNA repair and proliferation in breast cancers, its potential as a therapeutic target for breast cancer has not been assessed in terms of clinical outcomes. Thus, this study aims to analyze NR1D1 expression in breast cancer patients and to evaluate its potential prognostic value. Methods NR1D1 expression was analyzed by immunohistochemistry using an anti-NR1D1 antibody in 694 breast cancer samples. Survival analyses were performed using the Kaplan–Meier method with the log-rank test to investigate the association of NR1D1 expression with clinical outcome. Results One hundred thirty-nine of these samples exhibited high NR1D1 expression, mostly in the nucleus of breast cancer cells. NR1D1 expression correlated significantly with histological grade and estrogen receptor status. Overall survival (OS) and disease-free survival (DFS) did not correlate significantly with NR1D1 expression in breast cancer patients regardless of whether they had received chemotherapy. Subgroup analysis performed according to molecular subtype of breast cancer showed a significant influence of high NR1D1 expression on OS (P = 0.002) and DFS (P = 0.007) in patients with triple-negative breast cancer (TNBC) treated with chemotherapy. Conclusions High NR1D1 expression level had a favorable impact on OS and DFS in patients with TNBC treated with chemotherapy. NR1D1 should be investigated further as a possible prognostic marker in TNBC patients receiving chemotherapeutic treatment and as a target in the development of chemotherapeutic approaches to treating TNBC.

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Validation of the DNA Damage Immune Response Signature in Patients With Triple-Negative Breast Cancer From the SWOG 9313c Trial

Journal of Clinical Oncology ◽

10.1200/jco.19.00693 ◽

2019 ◽

Vol 37 (36) ◽

pp. 3484-3492 ◽

Cited By ~ 7

Author(s):

Priyanka Sharma ◽

William E. Barlow ◽

Andrew K. Godwin ◽

Eileen E. Parkes ◽

Laura A. Knight ◽

...

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Dna Damage ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Early Stage ◽

Statistical Significance ◽

Disease Free Survival ◽

Tumor Infiltrating Lymphocytes

PURPOSE To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313. METHODS Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size. RESULTS Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density ≥ 20% v < 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v < 20%). DDIR signature score and sTILs density were moderately correlated ( r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively. CONCLUSION The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.

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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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Chemotherapy-related outcomes in triple-negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e12049 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e12049-e12049

Author(s):

Rebecca M. Wellmann ◽

Sanaz N. Ghafouri ◽

Nicholas Patrick McAndrew ◽

Sara A. Hurvitz

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cox Regression ◽

Medical Center ◽

Academic Medical Center ◽

Disease Free Survival ◽

Free Survival ◽

Node Positive ◽

Increased Risk

e12049 Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis when compared to hormone receptor positive breast cancers. Anthracycline-based regimens (ABRs) are mainstays of treatment for non-metastatic TNBC. However, anthracyclines are associated with an increased risk of potentially life-threatening adverse effects. We sought to compare survival outcomes in patients with early TNBC treated with ABRs versus those treated with anthracycline-sparing regimens (ASRs). Methods: All patients treated for stage I-III TNBC who had undergone curative-intent surgery at a large academic medical center between January 2013-May 2018 were included in the study. Event-free survival (EFS) and disease-free survival (DFS) were the primary endpoints, with overall survival (OS) as a secondary endpoint and were defined as per standardized STEEP criteria. Kaplan-Meier, multivariable Cox regression, and log-rank tests were used to define key survival and treatment related differences between subjects treated with ABRs vs ASRs. Results: 137 patients met inclusion criteria with a median follow-up of 39 months. 21 patients (15%) recurred and 16 (12%) died. Patients treated with ABRs (n = 26, 19%) compared with ASRs (n = 111, 81%) had significantly shorter median EFS (38 months vs not-yet-reached, NYR, p < 0.001), DFS (37 months vs NYR, p < 0.001), and OS (50 months vs NYR, p < 0.001). Though patients in the ABR vs the ASR group were more likely to be node-positive (Odds Radio 3.46, p = 0.006), shorter survival estimates in the ABR group were observed after adjusting for nodal status. 27% of patients (7/26) had an anthracycline added after suboptimal response to an ASR. After adjusting for these patients, the survival findings were similar. 43 patients (31%) received a platinum containing ASR. In the platinum subgroup, ASRs were associated with longer EFS and DFS compared to ABRs, but this effect was not statistically significant in the node-positive group. No cardiac or secondary leukemic events were observed in either group. Conclusions: ABRs were associated with shorter EFS, DFS and OS, even after adjusting for certain high-risk clinical features. Larger studies are needed to identify the role of platinum containing ASRs in patients with early TNBC.

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Kinome-Wide siRNA Screening Identifies DYRK1B as a Potential Therapeutic Target for Triple-Negative Breast Cancer Cells

Cancers ◽

10.3390/cancers13225779 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5779

Author(s):

Chia-Che Chang ◽

Chien-Chih Chiu ◽

Pei-Feng Liu ◽

Chih-Hsuan Wu ◽

Yen-Chiang Tseng ◽

...

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Cell Viability ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Specific Inhibitor ◽

Disease Free Survival ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Normal Tissues

Aims: The selective molecules for targeted therapy of triple-negative breast cancer (TNBC) are limited. Several kinases play pivotal roles in cancer development and malignancy. The study aims to determine if any kinases confer to malignancy of TNBC cells, which could serve as a theranostic target for TNBC. Methods: Kinome siRNA library was used to screen selective genes required for the proliferation of TNBC cells. The involvement of DYRK1B in cancer malignancy was evaluated with migration, invasion assays, and spheroid culture. The expression of DYRK1B was confirmed with quantitative PCR and immunoblotting. The clinical correlation of DYRK1B in TNBC patients was examined with tissue microarray and The Cancer Genome Atlas (TCGA) database. Results: Our results showed that silencing DYRK1B significantly suppressed cell viability in DYRK1B-high expressed TNBC cells, likely by arresting the cell cycle at the G1 phase. Nevertheless, silencing DYRK1B had marginal effects on DYRK1B-low expressed TNBC cells. Similarly, the knockdown of DYRK1B decreased tumorsphere formation and increased cell death of the tumorsphere. Moreover, inactivation of DYRK1B by either specific inhibitor or ectopic expressing catalytic mutant of DYRK1B inhibited cell viability and metastatic characteristics, including migration and invasion. In addition, DYRK1B protein expression was elevated in tumor tissues compared to that in adjacent normal tissues of TNBC patients. Further, DYRK1B gene expression was highly correlated with CCDC97 or ZNF581 genes in TNBC cells and patients. High co-expression of DYRK1B with CCDC97 or ZNF581 was significantly associated with unfavorable overall survival and disease-free survival of TNBC patients. Conclusions: our results suggest DYRK1B might be essential for promoting tumor progression and could be a theranostic target for TNBC. Silencing or inactivation of DYRK1B might be a potential targeted therapy 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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