J Breast Cancer.  2016 Mar;19(1):53-60. 10.4048/jbc.2016.19.1.53.

High EZH2 Protein Expression Is Associated with Poor Overall Survival in Patients with Luminal A Breast Cancer

• Jang SH
• Lee JE
• Oh MH
• Lee JH
• Cho HD
• Kim KJ
• Kim SY
• Han SW
• Kim HJ
• Bae SB
• Lee HJ

• KMID: 2176321
• DOI: http://doi.org/10.4048/jbc.2016.19.1.53

Abstract

PURPOSE
The enhancer of zeste homologue 2 (EZH2) is a catalytic subunit of the polycomb repressive complex 2, a highly conserved histone methyltransferase. EZH2 overexpression has been implicated in various malignancies, including breast cancer, where is associated with poor outcomes. This study aims to clarify nuclear EZH2 expression levels in breast cancers using immunohistochemistry (IHC) and correlate these findings with clinicopathologic variables, including prognostic significance.
METHODS
IHC was performed on tissue microarrays of 432 invasive ductal carcinoma (IDC) tumors. Associations between EZH2 expression, clinicopathologic characteristics, and molecular subtype were retrospectively analyzed. The relationship between EZH2 protein expression in normal breast tissue and ductal carcinoma in situ (DCIS) was also assessed.
RESULTS
High EZH2 expression was demonstrated in 215 of 432 tumors (49.8%). EZH2 was more frequently expressed in DCIS and IDC than in normal breast tissue (p=0.001). High EZH2 expression significantly correlated with high histologic grade (p<0.001), large tumor size (p=0.014), advanced pathologic stage (p=0.006), negative estrogen receptor status (p<0.001), positive human epidermal growth factor receptor 2 (HER2) status (p<0.001), high Ki-67 staining index (p<0.001), positive cytokeratin 5/6 status (p=0.003), positive epidermal growth factor receptor status (p<0.001), and positive p53 status (p<0.001). Based on molecular subtypes, high EZH2 expression was significantly associated with HER2-negative luminal B, HER2-positive luminal B, and HER2 type and triple-negative basal cancers (p<0.001). In patients with luminal A, there was a significant trend toward shorter overall survival for those with tumors having high EZH2 expression compared to those with tumors having low EZH2 expression (p=0.045).
CONCLUSION
EZH2 is frequently upregulated in breast malignancies, and it may play an important role in cancer development and progression. Furthermore, EZH2 may be a prognostic marker, especially in patients with luminal A cancer.

Keyword

Breast neoplasms; Enhancer of zeste homologue 2; Immunohistochemistry; Prognosis

MeSH Terms

Breast Neoplasms*
Breast*
Carcinoma, Ductal
Carcinoma, Intraductal, Noninfiltrating
Catalytic Domain
Estrogens
Histones
Humans
Immunohistochemistry
Keratins
Phenobarbital*
Polycomb Repressive Complex 2
Prognosis
Receptor, Epidermal Growth Factor
Retrospective Studies
Estrogens
Histones
Keratins
Phenobarbital
Polycomb Repressive Complex 2
Receptor, Epidermal Growth Factor

Figure

• 

  Figure 1 Immunohistochemical analysis of enhancer of zeste homologue 2 (EZH2) expression in invasive ductal carcinoma of breast (×400): (A) normal breast tissue, (B) low, and (C) high expression. Note that EZH2 protein is expressed in the nuclei of cancer cells.

• 

  Figure 2 Mean enhancer of zeste homologue 2 (EZH2) expression score. Mean EZH2 expression score was significantly higher in malignant tumors than in normal breast tissues. Normal =normal breast tissue; DCIS =ductal carcinoma in situ; IDC=invasive ductal carcinoma.

• 

  Figure 3 Kaplan-Meier survival curve for enhancer of zeste homologue 2 (EZH2) (A, B) and molecular subtypes (C, D). (A) Disease-free survival (DFS, p=0.041) and (B) overall survival (OS, p=0.009) in breast cancer (n=432). Statistically significant differences among the molecular subtypes of (C) DFS and (D) OS. IDC=invasive ductal carcinoma; HER2=human epidermal growth factor receptor 2; TNBC=triple-negative breast cancer.

• 

  Figure 4 Kaplan-Meier survival curve for enhancer of zeste homologue 2 (EZH2) in patients with luminal A type disease (n=179). (A) Disease-free survival (p=0.142) and (B) overall survival (p=0.045).

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