Our study demonstrates a differential expression of HDAC1, HDAC2 and HDAC3 using immunohistochemistry in breast cancer. Expression of all three isoforms revealed significant correlations with clinicopathological parameters. Expression of HDAC2 and HDAC3 was significantly higher in less differentiated tumors as well as in tumors with negative hormone receptor status. Additionally, tumors with HER2 overexpression and positive lymph node metastasis showed a significant higher expression of HDAC2. In contrast, a high expression of the HDAC1 was found in hormone receptor positive tumors.
To our knowledge, this is the first time that the class-1 isoforms HDAC1, -2 and −3 were analyzed together in the same breast cancer cohort.
Krusche et al.  did an immunhistochemical analysis of the expression of HDAC1 and HDAC3 in 200 breast cancer samples. Similar to our findings, they found a significant correlation between positive HDAC1 expression and positive hormone receptor expression. In contrast to our results, they additionally described a correlation of HDAC3 with a positive hormone receptor expression. They found no significant results concerning the correlation of HDAC and grading.
Similarly with our findings, Zhang et al. showed similar results concerning HDAC1, with an increased HDAC1 mRNA expression in hormone receptor positive tumors .
Most interestingly, we could find a significantly higher expression of HDAC2 and −3 in more aggressive tumor types. Expression of HDAC2 and −3 was higher in poorly differentiated and hormone receptor negative tumors, for HDAC2 we also found a significant correlation with HER2 overexpression. This correlation of HDACs and clincopathological parameters, which mark a more aggressive tumor type, was shown in other histological cancer types before .
In accordance with our results other studies might also suggest a suppression of estrogen receptor by overexpression of HDAC. Several in vitro studies analyzed the reexpression of the estrogen receptor after therapy with Trichostatin A . Zhou et al.  achieved a restoring of estrogen receptor mRNA and protein expression. These findings suggest that estrogen receptor could be suppressed by enhanced HDAC activity and restored by HDAC inhibitors.
Additionally, multiple groups have analyzed the influence of HDAC inhibitors in estrogen receptor positive breast cancer. Here, treatment with HDAC inhibitors led to a down-regulation of estrogen receptor alpha [23, 24]. In contrast, the estrogen receptor beta was shown to increase the antiproliferative potential of HDAC inhibitors as well as apoptosis as analyzed by Duong et al. .
In clinical studies the combination of HDAC inhibitors and hormone therapy showed first effects. Munster et al. could show an response rate of 19% for the combination of Vorinostat and Tamoxifen  In contrast, the monotherapy with Tamoxifen in metastatic breast cancer achieved only a response rate below 10%.
Both, in vitro and in vivo studies show that HDAC2 could be a potential biomarker. Marchion et al. showed the selective inhibition of HDAC2 in breast cancer cells to be responsible for hyperacetylation of histones and proteins . In clinical studies tumors with HDAC2-expression showed a more acetylated histone status after therapy with Doxorubicin and Vorinostat . HDAC2 might therefore mark tumors with response to HDAC inhibitors.
In normal mammary gland, we saw a homogenous expression of the HDAC class I isoenzymes. Similar results are described by other groups .
Despite our long observation time (median: 158 months) we could not observe any prognostic influence of the expression of any of the HDAC isoenzymes in this retrospective analyses. This could be due to the influence of variable therapy regimens in this time as well as the missing parameters of disease-specific deaths. Other studies have described a prognostic role for HDAC1 in breast cancer . Due to the staining on a TMA, a possible heterogeneously expression of the analysed isoenzymes could be underrepresented.
Altogether, the interaction between the hormone receptor status and the HDAC expression as well as HDAC inhibitors are complex and need to be evaluated in further studies .