Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer - overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression

Jan Budczies,Lisa Jana,Carsten Denkert,Wilko Weichert,Klaus-Jürgen Winzer,Manfred Dietel,Annika Lehmann,Atsuko Kasajima,Berit Maria Müller,Judith Prinzler

doi:10.1186/1471-2407-13-215

Jan Budczies, Lisa Jana + Show 8 more

Open Access

https://doi.org/10.1186/1471-2407-13-215

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Abstract

BackgroundIn breast cancer, the role of epigenetic alterations including modifications of the acetylation status of histones in carcinogenesis has been an important research focus during the last years. An increased deacetylation of histones leads to increased cell proliferation, cell migration, angiogenesis and invasion. Class 1 histone deacetylases (HDAC) seem to be most important during carcinogenesis.MethodsThe immunhistochemical expression of HDAC1, 2 and 3 was analyzed on tissue microarrays (TMAs) from 238 patients with primary breast cancer. We analyzed the nuclear staining intensity (negative, weak, moderate, strong) as well as the percentage of positive tumor cells and calculated the immunoreactivity score (0–12). Expression was correlated with clinicopathological parameters and patient survival.ResultsIn this cohort, we found a differential positive expression of HDAC1, HDAC2 and HDAC3. HDAC2 and HDAC3 expression was significantly higher in less differentiated tumors: HDAC2 (n=207), p<0.001 and HDAC3 (n=220), p<0.001 and correlated with negative hormone receptor status: HDAC2 (n=206), p=0.02 and HDAC3 (n=219), p=0.04. Additionally, a high HDAC2 expression was significantly associated with an overexpression of HER2 (n=203, p=0.005) and the presence of nodal metastasis (n=200, p=0.04).HDAC1 was highly expressed in hormone receptor positive tumors (n=203; p<0.001).ConclusionAs a conclusion, our results show that the class-1 HDAC isoenzymes 1, 2 and 3 are differentially expressed in breast cancer. HDAC2 and HDAC3 are strongly expressed in subgroups of tumor with features of a more aggressive tumor type.

Highlights

In breast cancer, the role of epigenetic alterations including modifications of the acetylation status of histones in carcinogenesis has been an important research focus during the last years
Expression of histone deacetylases (HDAC) in breast cancer We could find a differential expression of HDAC1, HDAC2 and HDAC3 in this cohort
High (IRS 9–12) nuclear expression of HDAC1, HDAC2 and HDAC3 was observed in 32.7%, 24.1% and 31.7% of cases, respectively

Summary

Introduction

The role of epigenetic alterations including modifications of the acetylation status of histones in carcinogenesis has been an important research focus during the last years. An increased deacetylation of histones leads to increased cell proliferation, cell migration, angiogenesis and invasion. Class 1 histone deacetylases (HDAC) seem to be most important during carcinogenesis. Several studies about the role of epigenetic alterations including modifications of the acetylation status of histones in the development of human cancer have been published [2,3]. An increased deacetylation of histones leads to an increased cell proliferation, cell migration, angiogenesis and invasion by reducing the transcription of tumorsuppressor genes [4]. Among the HDAC inhibitors, which can be categorized based on their structure, suberoylanilide hydroxamic acid (SAHA) was first approved for therapy for cutaneous T-cell lymphoma in 2006 [10]

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