Dataset Information

Prognostic significance of nuclear expression of UMP-CMP kinase in triple negative breast cancer patients.

ABSTRACT: We have previously identified UMP-CMP kinase (CMPK1) as a prognostic marker for triple negative breast cancer (TNBC) by mass spectrometry (MS). In this study we evaluated CMPK1 association to prognosis in an independent set of samples by immunohistochemistry (IHC) and assessed biological pathways associated to its expression through gene set enrichment analysis (GSEA). A total of 461 TNBC paraffin-embedded tissues were collected from different academic hospitals in Europe, incorporated into tissue micro-arrays (TMA), and stained for CMPK1 expression. We also collected gene expression data of 60 samples, which were also present in the TMA, for GSEA correlation analysis. CMPK1 IHC staining showed both cytoplasmic and nuclear components. While cytoplasmic CMPK1 did not show any association to metastasis free survival (MFS), nuclear CMPK1 was associated to poor prognosis independently from other prognostic factors in stratified Cox regression analyses. GSEA correlation analysis of the nuclear CMPK1-stratified gene expression dataset showed a significant enrichment of extracellular matrix (ECM; positive correlation) and cell cycle (negative correlation) associated genes. We have shown here that nuclear CMPK1 is indicative of poor prognosis in TNBCs and that its expression may be related to dysregulation of ECM and cell cycle molecules.

SUBMITTER: Liu NQ

PROVIDER: S-EPMC4997324 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Prognostic significance of nuclear expression of UMP-CMP kinase in triple negative breast cancer patients.

Liu Ning Qing NQ De Marchi Tommaso T Timmermans Annemieke A Trapman-Jansen Anita M A C AM Foekens Renée R Look Maxime P MP Smid Marcel M van Deurzen Carolien H M CH Span Paul N PN Sweep Fred C G J FC Brask Julie Benedicte JB Timmermans-Wielenga Vera V Foekens John A JA Martens John W M JW Umar Arzu A

Scientific reports 20160825

We have previously identified UMP-CMP kinase (CMPK1) as a prognostic marker for triple negative breast cancer (TNBC) by mass spectrometry (MS). In this study we evaluated CMPK1 association to prognosis in an independent set of samples by immunohistochemistry (IHC) and assessed biological pathways associated to its expression through gene set enrichment analysis (GSEA). A total of 461 TNBC paraffin-embedded tissues were collected from different academic hospitals in Europe, incorporated into tiss ...[more]

PMID: 27558661

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Project description:BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous disease with a worse prognosis. However, current therapies have rarely improved the outcome of patients with TNBC. Here we sought to identify novel biomarkers or targets for TNBC.Materials and methodsPatients GSE76275 clinic traits and their corresponding mRNA profiles for 198 TNBC and 67 non-TNBC were obtained from the GEO database. Weighted gene co-expression network analysis (WGCNA) of the GSE76275 keyed out hub genes, and the differentially expressed genes (DEGs) were identified with the cut-off of adjusted P (adj. P) <0.01 and |log2 fold-change (FC)| > 1.5. The hub - DEGs overlapping genes, as key genes, were considered for further study using Kaplan-Meier plotter online analysis. Subsequently, Breast Cancer Gene-Expression Miner v4.0 and tissue microarray analysis were applied to determine the transcriptional and translational levels of every key gene. Following plasmid transfection for overexpression, the proliferation of TNBC cells was determined by CCK8 and colony formation assay. Moreover, xenograft tumor models were canvassed to investigate their effect upon in vivo tumor growth.ResultsFour genes (SIDT1, ANKRD30A, GPR160, and CA12) were found to be associated with relapse-free survival (RFS) in TNBC through WGCNA and DEGs integrated analysis. Patients with a higher level of SIDT1 had significantly better RFS compared to those with lower levels. The transcriptional and translational levels of SIDT1 were validated as downregulated in patients with triple-negative status, negative estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Furthermore, SIDT1 inhibited proliferation of breast cancer cells (MDA-MB-231 and MDA-MB-468) and xenograft studies demonstrated that SIDT1 can suppress tumor growth in vivo.ConclusionThis study suggests that SIDT1 may play a crucial role in TNBC progression and has the potential as a prognostic biomarker of TNBC.

Project description:Background:Triple Negative Breast Cancer (TNBC) represents a heterogeneous group of tumors with poor prognosis owing to aggressive tumor biology and lack of targeted therapies. No clear prognostic biomarkers have been identified to date for this subgroup. Materials and Methods:In this retrospective study we evaluated the prognostic role of 4 different molecular determinants, including androgen receptor (AR), E-cadherin (CDH1), Ki67 index, and basal cytokeratins (CKs) 5/6, in a cohort of 99 patients with TNBC. All patients received neo/adjuvant chemotherapy (mostly anthracycline/taxane-based). Immunohistochemistry (IHC) was performed in formalin-fixed paraffin-embedded primary tumor samples. CDH1 expression was considered positive as ? 30% of the membrane cells staining. AR positivity was defined as > 10% of positive tumor cells. High Ki67 was defined as ?20% positive tumor cells. CK5/6 expression was judged positive if the score was ?1. Results:The absence of AR expression was significantly associated with highly undifferentiated tumors. Univariate analyses showed that lack of expression of CDH1, tumor size and nodal status were significantly correlated with worse RFS and OS (p< 0.05). AR expression and low Ki67 showed a trend towards better RFS and OS. Patients with absent CK5/6 expression in univariate and multivariate analyses had poorer RFS (p=0.02 and p=0.002, respectively) and OS (p=0.05 and p=0.02, respectively). Multivariate analysis showed an independent association between CDH1 expression and better RFS and OS (p< 0.05) beyond tumor size, nodal status, and grade. The Kaplan-Meier curves showed that patients with AR and CDH1 negative expression and high Ki-67 levels have a significant correlation with poor outcome. Conclusions:Our study supports the use of IHC expression of AR, CDH1, Ki67, and CK5/6 as prognostic markers in TNBCs and suggests a link between their expression and prognosis and may help to stratify TNBC patients in different prognostic classes.

Dataset Information

Prognostic significance of nuclear expression of UMP-CMP kinase in triple negative breast cancer patients.

Publications

Prognostic significance of nuclear expression of UMP-CMP kinase in triple negative breast cancer patients.

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