Prognostic and therapeutic significance of ribonucleotide reductase small subunit M2 in estrogen-negative breast cancers.

Hang Zhang,Suzhan Zhang,Yasheng Huang,Xiyong Liu,Charles D Warden,Sofia Loera,Peiguo Chu,Yun Yen,Lijun Xue,Shu Zheng

doi:10.1186/1471-2407-14-664

Abstract

BackgroundRibonucleotide reductase (RR) is an essential enzyme involved in DNA synthesis. We hypothesized that RR subunit M2 (RRM2) might be a novel prognostic and predictive biomarker for estrogen receptor (ER)-negative breast cancers.MethodsIndividual and pooled survival analyses were conducted on six independent large-scale breast cancer microarray data sets; and findings were validated on a human breast tissue set (ZJU set).ResultsGene set enrichment analysis revealed that RRM2-high breast cancers were significantly enriched for expression of gene sets that increased in proliferation, invasiveness, undifferentiation, embryonic stem/progenitor-like phenotypes, and poor patient survival (p < 0.01). Independent and pooled analyses verified that increased RRM2 mRNA levels were associated with poor patient outcome in a dose-dependent manner. The prognostic power of RRM2 mRNA was comparable to multiple gene signatures, and it was superior to TNM stage. In ER-negative breast cancers, RRM2 showed more prognostic power than that in ER-positive breast cancers. Further analysis indicated that RRM2 was a more accurate prognostic biomarker for ER-negative breast cancers than the pathoclinical indicators and uPA. A new RR inhibitor, COH29, could significantly enhance the chemosensitivity to doxorubicin in ER-negative MDA-MB-231 cells, but not in ER-positive MCF-7 cells.ConclusionRRM2 appears to be a promising prognostic biomarker and therapeutic target for ER-negative breast cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-664) contains supplementary material, which is available to authorized users.

Highlights

Ribonucleotide reductase (RR) is an essential enzyme involved in DNA synthesis
Oncofetal characteristics of RR subunit M2 (RRM2) in breast cancers The Gene set enrichment analysis (GSEA) was conducted to determine the correlation between RRM2 expression and oncogenic pathways in the Desmedt set
Genes that were significantly enriched in RRM2-high breast cancer subgroups controlled cancer undifferentiation, Sarrio’s epithelial-mesenchymal transition, breast cancer progenitor-like phenotypes, proliferation gene signature, Chang’s core serum response gene signature, and the Naderi breast cancer prognosis gene signature (Figure 1A through 1 F)

Summary

Introduction

We hypothesized that RR subunit M2 (RRM2) might be a novel prognostic and predictive biomarker for estrogen receptor (ER)-negative breast cancers. Breast cancer is a heterogeneous disease that has variable gene expression and different outcomes that cannot be predicted by pathologic grade or clinical stages [2,3]. Predict the survival of breast cancer patients, and have been used to predict the outcome for ER-positive patients. A 7-gene immune response module (IRM) [13] and a HER2-derived prognostic predictor (HDPP, 158 genes) [14] were developed to identify ER-negative breast cancers that were associated with poor prognosis. Multiple-gene-based signatures potentially enhance the accuracy of prediction. Their disadvantages include higher cost and lack of specific targets for chemotherapeutic agent selection

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Discussion

Conclusion