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Abundant NDRG2 Expression Is Associated with Aggressiveness and Unfavorable Patients' Outcome in Basal-Like Breast Cancer.

ABSTRACT: NDRG2, a member of the N-myc downstream-regulated gene family, is thought to be a putative tumor suppressor gene with promising clinical impact in breast cancer. Since breast cancer comprises heterogeneous intrinsic subtypes with distinct clinical outcomes we investigated the pivotal role of NDRG2 in basal-type breast cancers. Based on subtype classified tumor (n = 45) and adjacent normal tissues (n = 17) we examined NDRG2 mRNA expression and CpG-hypermethylation, whose significance was further validated by independent data sets from The Cancer Genome Atlas (TCGA). In addition, NDRG2 protein expression was evaluated immunohistochemically using a tissue micro array (TMA, n = 211). In vitro, we investigated phenotypic effects caused by NDRG2 silencing in the basal A-like HCC1806 as well as NDRG2 over-expression in basal A-like BT20 compared to luminal-type MCF7 breast cancer cells. Our tissue collections demonstrated an overall low NDRG2 mRNA expression in breast cancer subtypes compared to normal breast tissue in line with an increased CpG-hypermethylation in breast cancer tissue. Independent TCGA data sets verified a significant (P<0.001) expression loss of NDRG2 in breast tumors. Of interest, basal-like tumors more frequently retained abundant NDRG2 expression concordant with a lower CpG-hypermethylation. Unexpectedly, basal-like breast cancer revealed an association of NDRG2 expression with unfavorable patients' outcome. In line with this observation, in vitro experiments demonstrated reduced proliferation and migration rates (~20%) in HCC1806 cells following NDRG2 silencing. In contrast, NDRG2 over-expressing luminal-type MCF7 cells demonstrated a 26% decreased proliferation rate. Until now, this is the first study investigating the putative role of NDRG2 in depth in basal-type breast cancer. Our data indicate that the described putative tumor suppressive function of NDRG2 may be confined to luminal- and basal B-type breast cancers.

SUBMITTER: Kloten V

PROVIDER: S-EPMC4939972 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Abundant NDRG2 Expression Is Associated with Aggressiveness and Unfavorable Patients' Outcome in Basal-Like Breast Cancer.

Kloten Vera V Schlensog Martin M Eschenbruch Julian J Gasthaus Janina J Tiedemann Janina J Mijnes Jolein J Heide Timon T Braunschweig Till T Knüchel Ruth R Dahl Edgar E

PloS one 20160711 7

NDRG2, a member of the N-myc downstream-regulated gene family, is thought to be a putative tumor suppressor gene with promising clinical impact in breast cancer. Since breast cancer comprises heterogeneous intrinsic subtypes with distinct clinical outcomes we investigated the pivotal role of NDRG2 in basal-type breast cancers. Based on subtype classified tumor (n = 45) and adjacent normal tissues (n = 17) we examined NDRG2 mRNA expression and CpG-hypermethylation, whose significance was further ...[more]

PMID: 27400234

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Project description:BackgroundBreast cancer is a potentially fatal malignancy in females despite the improvement in therapeutic techniques. The identification of novel molecular signatures is needed for earlier detection, monitoring effects of treatment, and predicting prognosis. We have previously used microarray analysis to identify differentially expressed genes in aggressive breast tumors. The purpose of the present study was to investigate the prognostic value of the candidate biomarkers CCNB2, ASPM, CDCA7, KIAA0101, and SLC27A2 in breast cancer.MethodsThe expression levels and subcellular localization of the CCNB2, ASPM, CDCA7, KIAA0101, and SLC27A2 proteins were measured using immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Furthermore, the mRNA levels of CCNB2, KIAA0101, and SLC27A2 were subsequently examined by qRT-PCR to validate IHC results. Patient disease-specific survival (DSS) was evaluated in correlation to protein levels using the Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the impact of aberrant protein expression of the candidate biomarkers on patient DSS and to estimate the hazard ratio at 8-year follow-up.ResultsElevated cytoplasmic CCNB2 protein levels were strongly associated with short-term disease-specific survival of breast cancer patients (≤ 8 years; P<0.001) and with histological tumor type (P= 0.04). However, no association with other clinicopathological parameters was observed. Multivariate Cox regression analysis specified that CCNB2 protein expression is an independent prognostic marker of DSS in breast cancer. The predictive ability of several classical clinicopathological parameters was improved when used in conjunction with CCNB2 protein expression (C-index = 0.795) in comparison with a model without CCNB2 expression (C-index = 0.698). The protein levels of ASPM, CDCA7, KIAA0101, and SLC27A2 did not correlate with any clinicopathological parameter and had no influence on DSS. However, a significant correlation between the expression of the CCNB2 and ASPM proteins was detected (P = 0.03).ConclusionThese findings suggest that cytoplasmic CCNB2 may function as an oncogene and could serve as a potential biomarker of unfavorable prognosis over short-term follow-up in breast cancer.

Project description:BackgroundLow-grade glioma (LGG) is susceptible to ferroptosis, which is involved in TMZ resistance. Ferroptosis induction can enhance the sensitivity to TMZ and synergistically kill glioma cells. T cell-promoted tumor ferroptosis is a vital anti-tumor mechanism of immune checkpoint inhibitors. The SAT1 activation is closely related to ferroptosis upon ROS induction due to the upregulation of arachidonate 15-lipoxygenase (ALOX15) expression.MethodsThe expression of SAT1 in pan-cancer and corresponding normal tissue from the TCGA data portal was primarily explored. The landscape of SAT1 and immune cell infiltration and their corresponding gene marker sets in different tissues were further explored. Additionally, we evaluated the relationships between SAT1 and the clinicopathologic parameters of LGG, and the disease-specific survival (DSS), progression-free interval (PFI), and overall survival (OS) were also assessed using KM survival curves and multivariate analysis in LGG. Meanwhile, the Gene Set Enrichment Analysis (GSEA) was also implemented to determine the potential effect of the SAT1 gene in LGG. Furthermore, the predictive power of SAT1 was validated using an independent LGG cohort from the Chinese Glioma Genome Atlas (CGGA) data.ResultsIn general, the expression of SAT1 is different between most tumors and their adjacent normal tissues. The results demonstrated that SAT1 expression is positively associated with TMB in LGG, BRCA, and THYM. The results displayed that the expression level of SAT1 is obviously correlated with the level of infiltrating macrophages and CD8 + T cells, and the levels of most immune gene sets were associated with the SAT1 expression in LGG. Interestingly, univariate and multivariate models significantly indicated that the OS and PFI of patients with LGG with high SAT1 levels were poorer than those with low SAT1 expression in the TCGA LGG cohort. GSEA showed that SAT1 was involved in immune regulation and multiple signaling pathways. Finally, our analysis demonstrated that SAT1 was closely associated with IDH mutation, 1p19q codeletion, chemoradiotherapy resistance and disease recurrence.ConclusionsAbundant expression of SAT1 was related to poor disease prognosis and abundant immune cell infiltration in LGG.

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Abundant NDRG2 Expression Is Associated with Aggressiveness and Unfavorable Patients' Outcome in Basal-Like Breast Cancer.

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Abundant NDRG2 Expression Is Associated with Aggressiveness and Unfavorable Patients' Outcome in Basal-Like Breast Cancer.

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