title: Epigenetic modifications, chromatin distribution and TP53 transcription in a model of breast cancer progression.
abstract: In the present paper we aimed to characterize epigenetic aspects and analyze TP53 transcription in the 21 T series, composed of breast cell lines: non-cancerous H16N2; Atypical Ductal Hyperplasia 21PT; Ductal Carcinoma in situ 21NT and Invasive Metastatic Carcinoma 21MT1. We detected a global genomic hypomethylation in 21NT and 21MT1. The histone modification markers analysis showed an important global decrease of the active chromatin mark H4Ac in 21MT1 relative to the other cell lines while the repressive mark H3K9Me3 were not significantly altered. The mRNA levels of DNA methylation and histone modification key enzymes are consistent with the observed genomic hypomethylation and histone hypoacetylation. The expression of DNMT3A/B increased at the initial stages of oncogenesis and the expression of DNMT1 and HAT1 decreased at the advanced stages of breast cancer. Using a confocal immunofluorescent assay, we observed that H4Ac was mostly located at the periphery and the repressive mark H3K9Me3, at the center of 21NT and 21MT1 cells nuclei. TP53 P1 promoter was found to be in an open chromatin state, with a relatively high enrichment of H4Ac and similar TP53 transcription levels in all 21 T cell lines. In conclusion, we observed epigenetic alterations (global genome hypomethylation, global hypoacetylation and accumulation of pericentric heterochromatin) in metastatic breast cancer cells of the 21 T series. These alterations may act at later stages of breast cancer progression and may not affect TP53 transcription at the P1 promoter.
authors.affiliation: Departamento de Genética, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 20550-013, Brazil; Université Paris-Sud 11 CNRS UMR 8126 «Signalisation, Noyaux et Innovations en Cancérologie», Institut de Cancérologie Gustave-Roussy, Université Paris-Sud 11, F-94805, Villejuif Cedex, France.
authors.forename: Gilson C
authors.initials: GC
authors.lastname: Santos
authors.forename: Ana P A
authors.initials: AP
authors.lastname: da Silva
authors.forename: Lucas
authors.initials: L
authors.lastname: Feldman
authors.forename: Grasiella M
authors.initials: GM
authors.lastname: Ventura
authors.forename: Yegor
authors.initials: Y
authors.lastname: Vassetzky
authors.forename: Claudia V
authors.initials: CV
authors.lastname: de Moura Gallo
mesh_terms: D000107:Acetylation; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D002843:Chromatin; D004273:DNA, Neoplasm; D006657:Histones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: 21T CELL LINES; BREAST CANCER PROGRESSION; DNA METHYLATION; EPIGENETICS; HISTONE ACETYLATION; TP53