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

Abstract

PurposeDNA 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.MethodsImmunohistochemical (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.ResultsHigh 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.ConclusionHDAC1 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.

MicroRNA (miR)‐433 and miR‐22 dysregulations induce histone‐deacetylase‐6 overexpression and ciliary loss in cholangiocarcinoma

“…The loss of primary cilia dysregulates tumorigenic signaling pathways like MAPK and Hh . Likewise, overexpression of HDAC6 has been reported in different types of tumors, such as breast cancer, melanoma, and pancreatic cancer . Liu et al found that HDAC6 was up‐regulated in both melanoma cells and tissues compared to normal skin cells and tissues .…”

A Decrease of Histone Deacetylase 6 Expression Caused by Helicobacter Pylori Infection is Associated with Oncogenic Transformation in Gastric Cancer

“…Moreover, the mechanism of HDAC6 expression in GC is still unclear. Some data have shown that low HDAC6 expression was associated with poor prognosis in breast cancer and hepatocellular carcinoma [9, 11]. This indicated HDAC6 as a tumor suppressor gene.…”

Transcriptional repression of human epidermal growth factor receptor 2 by ClC‐3 Cl−/H+ transporter inhibition in human breast cancer cells

“…Our previous study showed high expression levels of HDAC1, 2, 3, and 6 in both cell lines. 19 Seo et al 36 reported a positive correlation between HER2 and HDAC6, but not HDAC1, 2, or 3 in breast cancer cells. As shown in Figure 9G,N, no significant changes in the expression level of HDAC6 by the siRNA-mediated inhibition of ClC-3 or ANO1 were found in either cell line.…”