J Breast Cancer.  2014 Dec;17(4):323-331. 10.4048/jbc.2014.17.4.323.

Expression of Histone Deacetylases HDAC1, HDAC2, HDAC3, and HDAC6 in Invasive Ductal Carcinomas of the Breast

• Seo J
• Min SK
• Park HR
• Kim DH
• Kwon MJ
• Kim LS
• Ju YS

• KMID: 2176122
• DOI: http://doi.org/10.4048/jbc.2014.17.4.323

Abstract

PURPOSE
DNA deacetylation by histone deacetylase (HDAC) is an important mechanism involved in the oncogenic tumorigenesis of breast cancer. Previous studies have reported an association of the estrogen receptor (ER) with HDACs and demonstrated the efficacy of HDAC inhibitors for the treatment of breast cancers via in vitro experiments. In this study, we examined the association of HDAC expression with clinicopathological parameters and disease-specific survival.
METHODS
Immunohistochemical (IHC) analysis of HDAC1, HDAC2, HDAC3, and HDAC6 was performed using tissue microarrays in 300 invasive ductal carcinomas. IHC scoring was determined by multiplication of the intensity (0 to 3) and the proportion (0 to 4) of staining, and we classified tumors into low- and high-HDAC expression groups.
RESULTS
High expression of HDAC1 was correlated with the molecular subtype (p=0.001) and human epidermal growth factor 2 (HER2) amplification (p=0.012). High expression of HDAC6 was correlated with a younger age (p<0.001), ER expression (p=0.025), progesterone receptor expression (p=0.034), molecular subtype (p=0.023), and HER2 amplification (p=0.011). High HDAC1 expression was correlated with luminal A tumors (p=0.001), while high HDAC6 expression was more common in luminal B tumors (p=0.023). Although the expression of HDACs did not exhibit prognostic significance in the entire cohort, high expression of HDAC1 and HDAC6 was associated with improved overall survival (OS) in patients with ER-positive tumors (p=0.017 and p=0.029, respectively), and high expression of HDAC2 was correlated with improved OS in ER-negative tumors (p=0.048) on univariate analysis. Furthermore, high HDAC6 expression was associated with improved disease-free survival (p=0.048) on multivariate analysis.
CONCLUSION
HDAC1 expression is significantly correlated with the molecular subtypes of tumors, with the highest expression being observed in luminal A tumors. HDAC6 is a significantly correlated with ER expression and the molecular subtype, thereby supporting the estrogen regulatory property of HDAC6. HDAC1 and HDAC6 expression are good prognostic factors for ER-positive tumors.

Keyword

Breast neoplasms; Histone deacetylases; Immunohistochemistry

MeSH Terms

Breast Neoplasms
Breast*
Carcinogenesis
Carcinoma, Ductal*
Cohort Studies
Disease-Free Survival
DNA
Epidermal Growth Factor
Estrogens
Histone Deacetylase Inhibitors
Histone Deacetylases*
Humans
Immunohistochemistry
Multivariate Analysis
Phenobarbital
Receptors, Progesterone
DNA
Epidermal Growth Factor
Estrogens
Histone Deacetylase Inhibitors
Histone Deacetylases
Phenobarbital
Receptors, Progesterone

Figure

• 

  Figure 1 Immunohistochemical staining of histone deacetlylases (HDACs) in invasive ductal carcinomas (×400). (A) HDAC1 and (B) HDAC2 were expressed in the nuclei of tumor cells. (C) HDAC3 was observed in both the cytoplasm and the nuclei. (D) HDAC6 staining was observed in the cytoplasm.

• 

  Figure 2 Statistical analysis of histone deacetylase (HDAC) expression and survival using the Kaplan-Meier method. (A) High expression of HDAC1 was positively correlated with good overall survival (OS) in the estrogen receptor (ER)-positive group (long-rank test, p=0.017). (B) High expression of HDAC2 was associated with prolonged OS in ER-negative tumors (long-rank test, p=0.048). (C) In patients with ER-positive tumors, the expression of HDAC6 was significantly associated with increased OS (log-rank test, p=0.029). (D) In luminal B tumors, HDAC6 expression predicted good OS (log-rank test, p=0.001). (E) In patients with ER-positive tumors, the expression of HDAC6 was significantly associated with better disease-free survival (log-rank test, p=0.021). (F) HDAC6 expression also predicted prolonged disease-free survival in luminal B tumors (log-rank test, p=0.001).

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