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Journal of Breast Cancer Journal of J Breast Cancer 2017 June; 20(2): 132-141 https://doi.org/10.4048/jbc.2017.20.2.132 Breast Cancer ORIGINAL ARTICLE Overexpression of Uridine-Cytidine Kinase 2 Correlates with Breast Cancer Progression and Poor Prognosis Guosong Shen*, Pingya He*, Yingying Mao1, Peipei Li2, Frank Luh3,4, Guohui Ding5, Xiyong Liu3, Yun Yen6 Prenatal Diagnostic Center, Huzhou Women and Children Hospital, Huzhou; 1Department of Epidemiology and Biostatistics, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou; 2Hangzhou Hope Biotechnology Company, Hangzhou, China; 3Biomarkers Development, California Cancer Institute, Sino-American Cancer Foundation, Temple City, USA; 4General Medicine Division, College of Medicine, Taipei Medical University, Taipei, Taiwan; 5Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; 6Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan Purpose: Uridine-cytidine kinase (UCK) 2 is a rate-limiting enzyme UCK2 levels were correlated with estrogen receptor negativity involved in the salvage pathway of pyrimidine-nucleotide biosyn- (p<0.001), advanced tumor grade (p<0.001), and poor tumor thesis. Recent studies have shown that UCK2 is overexpressed differentiation (p<0.001). GSEA revealed that UCK2-high breast in many types of cancer and may play a crucial role in activating cancers were enriched for gene sets associated with metasta- antitumor prodrugs in human cancer cells. In the current study, sis, progenitor-like phenotypes, and poor prognosis. Multivariable we evaluated the potential prognostic value of UCK2 in breast Cox proportional hazards regression analyses of microarray cancer. Methods: We searched public databases to explore as- datasets verified that high UCK2 gene expression was associated sociations between UCK2 gene expression and clinical parame- with poor overall survival in a dose-response manner. The ters in patients with breast cancer. Gene set enrichment analysis prognostic power of UCK2 was superior to that of TNM staging (GSEA) was performed to identify biological pathways associated and comparable to that of multiple gene signatures. Conclusion: with UCK2 gene expression levels. Survival analyses were per- These findings suggest thatUCK2 may be a promising prognos- formed using 10 independent large-scale breast cancer microar- tic biomarker for patients with breast cancer. ray datasets. Results: We found that UCK2 mRNA expression was elevated in breast cancer tissue compared with adjacent nontumorous tissue or breast tissue from healthy controls. High Key Words: Biomarkers, Breast neoplasms, Prognosis, Uridine-cytidine kinase 2 INTRODUCTION rate of breast cancer has continued to decline over the last two decades in many countries worldwide. However, the 5-year Breast cancer is the second leading cause of malignancy relative survival rate for metastatic breast cancer remains rela- among women worldwide, with an estimated 1.67 million tively low [2]. On the molecular level, breast cancer encom- new cases and 522,000 deaths in 2012 [1]. As a result of im- passes a heterogeneous group of diseases with distinct clinical provements in early detection and treatment, the mortality differences in prognosis and response to therapy [3,4]. Estro- gen receptor (ER), progesterone receptor, and human epider- Correspondence to: Yingying Mao Department of Epidemiology and Biostatistics, School of Basic Medical mal growth factor receptor 2 (HER2) statuses are widely used Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou as biomarkers to aid in treatment selection and prediction of 310053, China prognosis in patients with breast cancer. For example, the use Tel: +86-571-8663-3305, Fax: +86-571-8663-3305 E-mail: [email protected] of HER2 as a predictive biomarker has been successful in the treatment of HER2-enriched tumors with trastuzumab [5]. *These authors contributed equally to this work. Despite the remarkable clinical response achieved with the This work was supported by grants from Natural Science Foundation of Zhejiang Province (LQ15H260001), National Natural Science Foundation of use of biomarkers such as HER2, there is still a critical need China (81602917), and Rencai Program of Zhejiang Chinese Medical for better prognostic and therapeutic biomarkers for efficient University (2014ZR06). treatment of breast cancer. Recently, gene signatures such as Received: November 4, 2016 Accepted: May 6, 2017 the 70-gene signature [6], wound-response gene signature [7], © 2017 Korean Breast Cancer Society. All rights reserved. http://ejbc.kr | pISSN 1738-6756 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ eISSN 2092-9900 licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Uridine-Cytidine Kinase 2 and Breast Cancer Prognosis 133 and 21-gene recurrence score [8] have been developed to pre- Associations of UCK2 gene expression with clinical outcome dict patient outcomes. These multiple-gene-based signatures of patients with breast cancer potentially increase prediction accuracy, but the disadvantages To investigate the associations of UCK2 expression with his- include the high cost of testing and lack of specific targets for tological grades, molecular subtypes, and clinical outcomes of chemotherapeutic agents. patients with breast cancer, we then searched the GOBO data- UCK2, located on chromosome 1q22-23.2, was initially base (Gene Expression-based Outcome for Breast Cancer identified as human testis-specific gene TSA903. It encodes Online; http://co.bmc.lu.se/gobo; accessed on October 9, uridine-cytidine kinase (UCK) 2, which is a rate-limiting en- 2015), which included microarray profiling data from 1,881 zyme involved in the salvage pathway of pyrimidine-nucleo- patients with breast cancer [14]. To further evaluate the prog- tide biosynthesis. UCK2 catalyzes the phosphorylation of uri- nostic and predictive value of UCK2 expression in breast can- dine and cytidine to form uridine monophosphate (UMP) and cer, 10 microarray datasets containing survival information of cytidine monophosphate (CMP) with efficiency 15- to 20-fold patients with breast cancer, including GSE1456 [15], GSE2034 higher than that of ubiquitously expressed isozyme UCK1 [9]. [16], GSE4922 [17], GSE7390 [18], NKI [19], GSE10885 [20], It also catalyzes the phosphorylation of several cytotoxic ribo- GSE22226 [21], GSE24450 [22], GSE25066 [23], GSE53031 nucleoside analogs that have been investigated for possible use [24], and GSE58812 [25], were downloaded from the Gene as chemotherapeutic agents for cancer treatment [10]. In add- Expression Omnibus. Detailed information regarding the mi- ition, UCK2 may be important for the pharmacological activa- croarray datasets used in the survival analysis is summarized tion of uridine and cytidine base analogs, such as the clinically in Supplementary Table 1 (available online). used analog 5-fluorouracil (5-FU). The level of UCK2 activity may be associated with cellular sensitivity to the nucleoside an- Gene set enrichment analysis alogs, as loss of UCK2 activity has been observed in cells resis- To evaluate the correlations between UCK2 expression and tant to the nucleoside analogs [9]. Interestingly, several previ- cancer-related pathways, gene set enrichment analysis (GSEA) ous studies have suggested that UCK2 activity is increased in was performed using the above mentioned breast cancer mi- cancer cells compared with normal tissue [11,12]. croarray data sets. The detailed protocol for GSEA is available In the current study, we performed expression profiling on the Broad Institute Gene Set Enrichment Analysis website analyses of UCK2 in breast cancer using publicly available da- (http://www.broad.mit.edu/gsea). Briefly, GSEA is a computa- tabases and microarray datasets. We found that UCK2 expres- tional method that determines whether a priori defined set of sion was correlated with clinical parameters in patients with genes shows statistically significant, concordant differences -be breast cancer, and its prognostic value was superior to TNM tween two biological states [26]. Data sets and phenotype label staging and comparable to multiple gene signatures. files were created and loaded into GSEA software (v2.0.13; Broad Institute, Cambridge, USA). The gene sets were down- METHODS loaded from the Broad Institute website. The phenotype label was UCK2-high versus UCK2-low. The number of permuta- Differential expression of UCK2 gene in breast cancer tissues tions was set to 1000. A ranked-list metric was generated by We first searched the Oncomine database (http://www.on- calculating the signal-to-noise ratio, which is based on the dif- comine.org; accessed on October 6th, 2015) using key words ference of means scaled according to the standard deviation. gene: “UCK2,” cancer type: “breast cancer” and analysis type: “cancer vs. normal” to assess whether UCK2 expression was al- Statistical analyses tered in breast cancer tissue. The search returned a total of 80 All statistical analyses were performed using SAS statistical comparisons in 15 breast cancer studies. Details regarding tis- software, version 9.2 (SAS Institute Inc., Cary, USA), unless sue collection and the experimental
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