title: 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.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  In 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).
  
  
  CONCLUSIONS
  As 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.
authors.affiliation: Institute of Pathology, Charité University Hospital, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany. berit.mueller@charite.de
authors.forename: Berit Maria
authors.initials: BM
authors.lastname: Müller
authors.forename: Lisa
authors.initials: L
authors.lastname: Jana
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kasajima
authors.forename: Annika
authors.initials: A
authors.lastname: Lehmann
authors.forename: Judith
authors.initials: J
authors.lastname: Prinzler
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.forename: Klaus-Jürgen
authors.initials: KJ
authors.lastname: Winzer
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology* / Q000556:secondary; D018275:Carcinoma, Lobular / Q000201:enzymology* / Q000556:secondary; D018450:Disease Progression; D005260:Female; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D060787:Neoplasm Grading; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D046888:Tissue Array Analysis; D000099186:Histone Deacetylase 3
chemical_list: D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000099186:Histone Deacetylase 3; C508053:ERBB2 protein, human; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human