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Global Histone Modifications in Breast Cancer Correlate with Tumor Phenotypes, Prognostic Factors, and Patient Outcome

¹ Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham and Nottingham Universities Hospital Trust, Schools of ² Pharmacy and ³ Computer Science, ⁴ Division of Epidemiology and Public Health, and ⁵ School of Molecular Medical Sciences, Institute of Infection, Immunity and Inflammation, University of Nottingham; ⁶ Division of Life Sciences, Nottingham Trent University, Nottingham, United Kingdom; ⁷ Department of Pathology, Faculty of Medicine, Menoufyia University, Menoufyia, Egypt; ⁸ Department of Pathology, Faculty of Medicine, Asuit University, Asuit, Egypt; and ⁹ Department of Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

Requests for reprints: Ian O. Ellis, Department of Histopathology, Nottingham Universities Hospitals City Campus, Hucknall Road, Nottingham NG5 1PB, United Kingdom. Phone: 44-115-9691169, ext. 56875; Fax: 440-115-9627768; E-mail: ian.ellis{at}nottingham.ac.uk.

Key Words: Histone • Breast cancer • Immunohistochemistry • Immunofluorescence • Western blot

Post-translational histone modifications are known to be altered in cancer cells, and loss of selected histone acetylation and methylation marks has recently been shown to predict patient outcome in human carcinoma. Immunohistochemistry was used to detect a series of histone lysine acetylation (H3K9ac, H3K18ac, H4K12ac, and H4K16ac), lysine methylation (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) marks in a well-characterized series of human breast carcinomas (n = 880). Tissue staining intensities were assessed using blinded semiquantitative scoring. Validation studies were done using immunofluorescence staining and Western blotting. Our analyses revealed low or absent H4K16ac in the majority of breast cancer cases (78.9%), suggesting that this alteration may represent an early sign of breast cancer. There was a highly significant correlation between histone modifications status, tumor biomarker phenotype, and clinical outcome, where high relative levels of global histone acetylation and methylation were associated with a favorable prognosis and detected almost exclusively in luminal-like breast tumors (93%). Moderate to low levels of lysine acetylation (H3K9ac, H3K18ac, and H4K12ac), lysine (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) were observed in carcinomas of poorer prognostic subtypes, including basal carcinomas and HER-2-positive tumors. Clustering analysis identified three groups of histone displaying distinct pattern in breast cancer, which have distinct relationships to known prognostic factors and clinical outcome. This study identifies the presence of variations in global levels of histone marks in different grades, morphologic types, and phenotype classes of invasive breast cancer and shows that these differences have clinical significance. [Cancer Res 2009;69(9):3802–9]