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Ecotropic virus integration-1 and calreticulin as novel prognostic markers in triple-negative breast cancer: A retrospective cohort study.

ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, for which no specific targete d therapy is currently available. The present study aimed to examine the associations of ecotropic virus integration site 1 (EVI-1) and calreticulin (CRT) with other clinicopathological variables and the prognosis of patients with TNBC. The present retrospective cohort study reviewed the medical records of patients with TNBC treated in the Affiliated Hospitals of Jinzhou Medical University between January 2010 and June 2015. The protein expression levels of EVI-1 and CRT in tumor samples obtained from the patients were examined by immunohistochemical analysis. Univariate and multivariate regression analyses were used to identify associations between clinical characteristics and disease-free survival (DFS) or overall survival (OS). Kaplan-Meier analysis was performed to observe the survival condition (DFS/OS) according to EVI-1 and CRT expression. A total of 88 TNBC patients were included in the present study. Tumor tissues in 52 (59.1%) patients were EVI-1 positive, and tumor tissues in 64 (72.7%) patients were CRT-positive, and these rates were significantly higher compared with those in the corresponding paracancerous tissues (P<0.05). Multivariate analysis revealed that EVI-1 and CRT expression levels were independent variables associated with OS and DFS, and high expression of both CRT and EVI-1 was significantly associated with decreased OS and DFS compared with the other subgroups (low EVI-1/low CRT expression, low EVI-1/high CRT expression and high EVI-1/low CRT expression) of patients with TNBC. EVI-1 and CRT expression in TNBC was significantly correlated with poor outcome. Evaluation of the EVI-1 and CRT status may provide insight into prognosis prediction for patients with TNBC.

SUBMITTER: He D

PROVIDER: S-EPMC6607142 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Ecotropic virus integration-1 and calreticulin as novel prognostic markers in triple-negative breast cancer: A retrospective cohort study.

He Dongning D Wu Lei L Li Xiaoxi X Liu Xiaodan X Ma Ping P Juang Youhong Y

Oncology letters 20190612 2

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, for which no specific targete d therapy is currently available. The present study aimed to examine the associations of ecotropic virus integration site 1 (EVI-1) and calreticulin (CRT) with other clinicopathological variables and the prognosis of patients with TNBC. The present retrospective cohort study reviewed the medical records of patients with TNBC treated in the Affiliated Hospitals of Jinzhou Medical University ...[more]

PMID: 31423253

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Project description:Triple-negative breast cancer (TNBC) is a heterogeneous group of tumours in which chemotherapy, the current mainstay of systemic treatment, is often initially beneficial but with a high risk of relapse and metastasis. There is currently no means of predicting which TNBC will relapse. We tested the hypothesis that the biological properties of normal stem cells are re-activated in tumour metastasis and that, therefore, the activation of normal mammary stem cell-associated gene sets in primary TNBC would be highly prognostic for relapse and metastasis.Mammary basal stem and myoepithelial cells were isolated by flow cytometry and tested in low-dose transplant assays. Gene expression microarrays were used to establish expression profiles of the stem and myoepithelial populations; these were compared to each other and to our previously established mammary epithelial gene expression profiles. Stem cell genes were classified by Gene Ontology (GO) analysis and the expression of a subset analysed in the stem cell population at single cell resolution. Activation of stem cell genes was interrogated across different breast cancer cohorts and within specific subtypes and tested for clinical prognostic power.A set of 323 genes was identified that was expressed significantly more highly in the purified basal stem cells compared to all other cells of the mammary epithelium. A total of 109 out of 323 genes had been associated with stem cell features in at least one other study in addition to our own, providing further support for their involvement in the biology of this cell type. GO analysis demonstrated an enrichment of these genes for an association with cell migration, cytoskeletal regulation and tissue morphogenesis, consistent with a role in invasion and metastasis. Single cell resolution analysis showed that individual cells co-expressed both epithelial- and mesenchymal-associated genes/proteins. Most strikingly, we demonstrated that strong activity of this stem cell gene set in TNBCs identified those tumours most likely to rapidly progress to metastasis.Our findings support the hypothesis that the biological properties of normal stem cells are drivers of metastasis and that these properties can be used to stratify patients with a highly heterogeneous disease such as TNBC.

Project description:BackgroundThe persistence of residual tumour after neoadjuvant chemotherapy (NAC) in localised triple-negative breast cancer (TNBC) is known to have a negative prognostic value. However, different degrees of expression of some immunohistochemical markers may correlate with different prognoses.MethodsThe expression of biomarkers with a known prognostic value, i.e., cytokeratin 5/6 (CK5/6), androgen receptor (AR), epidermal growth factor receptor (EGFR) proliferation-related nuclear antigen Ki-67, human epidermal growth factor receptor 2 (HER2), protein 53 (p53), forkhead box protein 3 (FOXP3), and cluster differentiation 8 (CD8), was analysed by immunohistochemistry in 111 samples after NAC in non-metastatic TNBC patients addressed to Georges-François Leclerc Cancer Centre Dijon, France. Clinical and pathological variables were retrospectively collected. Cox regression was used to identify immunohistochemical (IHC) and clinicopathological predictors of event-free survival (EFS) (relapse or death).ResultsMedian age was 50.4 years (range 25.6-88.3), 55.9% (n = 62) were non-menopausal, 70 (63.1%) had stage IIA-IIB disease. NAC was mostly sequential anthracycline-taxanes (72.1%), and surgical intervention was principally conservative (51.3%). We found 65.7% ypT1, 47.2% lymph node involvement (ypN+), and 29.4% lymphovascular invasion (LVI). Most residual tumours were EGFR >110 (H-score) (60.5%, n = 66), AR ≥4% (53.2%, n = 58), p53-positive mutated (52.7%, n = 58), CD8 ≥26 (58.1%, n = 61), FOXP3 ≥7 (51.4%, n = 54), more than half in the stroma, and 52.3% (n = 58) HER2 score 0. After a median follow-up of 80.8 months, 48.6% had relapsed. Median EFS was 62.3 months (95% CI, 37.2-not reached (NR)). Factors independently associated with poor EFS were AR-low (p = 0.002), ypN+ (p < 0.001), and LVI (p = 0.001). Factors associated with lower overall survival (OS) were EGFR-low (p = 0.041), Ki-67 high (p = 0.024), and ypN+ (p < 0.001).ConclusionPost-NAC residual disease in TNBC showed biomarkers specific to a basal-like subtype and markers of lymphocyte infiltration mostly present in the stroma. Prognostic markers for EFS were AR, LVI, and ypN and warrant further validation in a prognostic model.

Project description:BackgroundTo investigate the global expression profile of miRNAs, their impact on cellular signaling pathways, and their association with poor prognostic parameters in African-American (AA) patients with triple negative breast cancer (TNBC).MethodsTwenty-five samples of AA TNBC patients were profiled for global miRNA expression and stratified considering three clinical-pathological parameters: tumor size, lymph node (LN), and recurrence (REC) status. Differential miRNA expression analysis was performed for each parameter, and their discriminatory power was determined by Receiver Operating Characteristic (ROC) curve analysis. KMplotter was assessed to determine the association of the miRNAs with survival, and functional enrichment analysis to determine the main affected pathways and miRNA/mRNA target interactions.ResultsA panel of eight, 23 and 27 miRNAs were associated with tumor size, LN, and REC status, respectively. Combined ROC analysis of two (miR-2117, and miR-378c), seven (let-7f-5p, miR-1255b-5p, miR-1268b, miR-200c-3p, miR-520d, miR-527, and miR-518a-5p), and three (miR-1200, miR-1249-3p, and miR-1271-3p) miRNAs showed a robust discriminatory power based on tumor size (AUC = 0.917), LN (AUC = 0.945) and REC (AUC = 0.981) status, respectively. Enrichment pathway analysis revealed their involvement in proteoglycans and glycan and cancer-associated pathways. Eight miRNAs with deregulated expressions in patients with large tumor size, positive LN metastasis, and recurrence were significantly associated with lower survival rates. Finally, the construction of miRNA/mRNA networks based in experimentally validated mRNA targets, revealed nodes of critical cancer genes, such as AKT1, BCL2, CDKN1A, EZR and PTEN.ConclusionsAltogether, our data indicate that miRNA deregulated expression is a relevant biological factor that can be associated with the poor prognosis in TNBC of AA patients, by conferring to their TNBC cells aggressive phenotypes that are reflected in the clinical characteristics evaluated in this study.

Dataset Information

Ecotropic virus integration-1 and calreticulin as novel prognostic markers in triple-negative breast cancer: A retrospective cohort study.

Publications

Ecotropic virus integration-1 and calreticulin as novel prognostic markers in triple-negative breast cancer: A retrospective cohort study.

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