J Breast Cancer.  2017 Jun;20(2):132-141. 10.4048/jbc.2017.20.2.132.

Overexpression of Uridine-Cytidine Kinase 2 Correlates with Breast Cancer Progression and Poor Prognosis

• Shen G
• He P
• Mao Y
• Li P
• Luh F
• Ding G
• Liu X
• Yen Y

• KMID: 2389750
• DOI: http://doi.org/10.4048/jbc.2017.20.2.132

Abstract

PURPOSE
Uridine-cytidine kinase (UCK) 2 is a rate-limiting enzyme involved in the salvage pathway of pyrimidine-nucleotide biosynthesis. Recent studies have shown that UCK2 is overexpressed in many types of cancer and may play a crucial role in activating antitumor prodrugs in human cancer cells. In the current study, we evaluated the potential prognostic value of UCK2 in breast cancer.
METHODS
We searched public databases to explore associations between UCK2 gene expression and clinical parameters in patients with breast cancer. Gene set enrichment analysis (GSEA) was performed to identify biological pathways associated with UCK2 gene expression levels. Survival analyses were performed using 10 independent large-scale breast cancer microarray 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 UCK2 levels were correlated with estrogen receptor negativity (p<0.001), advanced tumor grade (p<0.001), and poor tumor differentiation (p<0.001). GSEA revealed that UCK2-high breast cancers were enriched for gene sets associated with metastasis, progenitor-like phenotypes, and poor prognosis. Multivariable Cox proportional hazards regression analyses of microarray datasets verified that high UCK2 gene expression was associated with poor overall survival in a dose-response manner. The prognostic power of UCK2 was superior to that of TNM staging and comparable to that of multiple gene signatures.
CONCLUSION
These findings suggest that UCK2 may be a promising prognostic biomarker for patients with breast cancer.

Keyword

Biomarkers; Breast neoplasms; Prognosis; Uridine-cytidine kinase 2

MeSH Terms

Biomarkers
Breast Neoplasms*
Breast*
Dataset
Estrogens
Gene Expression
Humans
Neoplasm Metastasis
Neoplasm Staging
Phenotype
Prodrugs
Prognosis*
RNA, Messenger
Uridine Kinase*
Biomarkers
Estrogens
Prodrugs
RNA, Messenger
Uridine Kinase

Figure

• 

  Figure 1 Expression analyses of UCK2 gene in patients with breast cancer. (A) UCK2 expression in breast cancer tissues relative to controls from the Oncomine database. Analyses showing p-values <10−5 and fold change values >|2| are marked in red. The size of the circle is scaled by the sample size of the corresponding analysis. (B) One array study E-TABM-276 comparing UCK2 expression in breast tissues from patients with breast cancer to UCK2 expression in breast tissues from healthy controls was identified in the Array Express database. The median normalized log2 expression values of UCK2 were 3.6 in breast tissues from healthy controls, 5.6 in tumor adjacent normal tissues, 6.4 in tissues exhibiting cystic change, and 7.4 in invasive breast cancer tissues. *Indicated p-value less than 0.05.

• 

  Figure 2 Association of UCK2 gene expression with tumor characteristics. UCK2 gene expression was associated with molecular subtypes (A), tumor grade (B) and estrogen receptor (ER) status (C) in patients with breast cancer using the GOBO (Gene Expression-based Outcome for Breast Cancer Online) database. The top row each figure indicates the number of patients with breast cancer in the analyses. HER2=human epidermal growth factor receptor 2; Lum=luminal.

• 

  Figure 3 Enriched gene signatures associated with aggressiveness and prognosis in UCK2-high and -low breast cancers. Normalized enrichment score (NES) represents the NES for the gene-set enrichment analyses. The ranked list metric was generated by calculating the signal-to-noise ratio, which is based on the difference of means scaled according to the standard deviation. The larger the signal-to-noise ratio, the more distinct the gene expression is for each phenotype. The heat maps show the enrichment of genes in the gene sets. Columns are individual samples and rows represent each gene. Blue indicates a low level of expression, and red indicates a high level of expression. (A, B) are the examples showing that UCK2 expression levels were inversely associated with breast cancer prognosis, and (C) shows the genes coexpressed with UCK2 were enriched in biological pathways associated with tumor grade, molecular subtype, cancer invasiveness, metastasis, and prognosis.

• 

  Figure 4 The prognostic significance of UCK2 in breast cancer. Multivariable Cox regression analyses of UCK2 with overall survival (OS) (A) and disease-free survival (DFS) (B) in patients with adjustment for age, grade and estrogen receptor (ER) status. Cox regression analyses of UCK2 with OS in patients with ER− (C) and ER+ (D) breast cancer, respectively. Multivariable analyses of UCK2 with DFS in patients with ER− (E) and ER+ (F) breast cancer, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for age and grade for (C–F).

• 

  Figure 5 The prognostic performances of UCK2 expression, the 70-gene signature, the wound-response gene signature, the 21-gene recurrence score, and the TNM staging in patients with estrogen receptor (ER)+ breast cancer in the NKI dataset using multivariable Cox proportional hazards regression models. (A) Overall survival (OS).(B) Disease-free survival (DFS). HR=hazard ratio; CI=confidence interval; WR=wound-response.

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