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Methylation of homeobox genes is a frequent and early epigenetic event in breast cancer.

ABSTRACT: Aberrant methylation of CpG islands is a hallmark of cancer and occurs at an early stage in breast tumorigenesis. However, its impact on tumor development is not fully determined, and its potential as a diagnostic biomarker remains to be validated. Methylation profiling of invasive breast carcinoma has been largely explored. Conversely, very little and sparse information is available on early-stage breast cancer. To gain insight into the epigenetic switches that may promote and/or contribute to the initial neoplastic events during breast carcinogenesis, we have analyzed the DNA methylation profile of ductal carcinoma in situ, a premalignant breast lesion with a great potential to progress toward invasive carcinoma.We have utilized a comprehensive and sensitive array-based DNA mapping technique, the methylated-CpG island recovery assay, to profile the DNA methylation pattern in ductal carcinoma in situ. Differential methylation of CpG islands was compared genome-wide in tumor DNA versus normal DNA utilizing a statistical linear model in the LIMMA software package.Using this approach, we have identified 108 significant CpG islands that undergo aberrant DNA methylation in ductal carcinoma in situ and stage I breast tumors, with methylation frequencies greater than or comparable with those of more advanced invasive carcinoma (50% to 93%). A substantial fraction of these hypermethylated CpG islands (32% of the annotated CpG islands) is associated with several homeobox genes, such as the TLX1, HOXB13, and HNF1B genes. Fifty-three percent of the genes hypermethylated in early-stage breast cancer overlap with known Polycomb targets and include homeobox genes and other developmental transcription factors.We have identified a series of new potential methylation biomarkers that may help elucidate the underlying mechanisms of breast tumorigenesis. More specifically, our results are suggestive of a critical role of homeobox gene methylation in the insurgence and/or progression of breast cancer.

SUBMITTER: Tommasi S

PROVIDER: S-EPMC2687719 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Methylation of homeobox genes is a frequent and early epigenetic event in breast cancer.

Tommasi Stella S Karm Deborah L DL Wu Xiwei X Yen Yun Y Pfeifer Gerd P GP

Breast cancer research : BCR 20090227 1

<h4>Introduction</h4>Aberrant methylation of CpG islands is a hallmark of cancer and occurs at an early stage in breast tumorigenesis. However, its impact on tumor development is not fully determined, and its potential as a diagnostic biomarker remains to be validated. Methylation profiling of invasive breast carcinoma has been largely explored. Conversely, very little and sparse information is available on early-stage breast cancer. To gain insight into the epigenetic switches that may promote ...[more]

PMID: 19250546

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Project description:Subpopulations of primary Human Mammary Epithelial Cells (HMEC) have the unique ability to escape a period of growth arrest and continue to proliferate. These cells, called post-selection or variant cells (vHMEC), share features with premalignant breast cancer lesions, including p16INK4A promoter hypermethylation. Epigenetic silencing of tumour suppressor genes through DNA methylation and histone modification is an early event in tumorigenesis. One of the main challenges is to find genes or gene pathways that are commonly silenced to provide early epigenetic diagnostic and therapeutic cancer targets. To identify very early epigenetic events that occur in breast cancer, we used microarrays to screen for gene pathways that were suppressed in post-selection HMECs, but reactivated after treatment with the demethylation agent 5-Aza-2’-deoxycytidine (5-Aza-dC). We found several members of the Transforming Growth Factor Beta (TGFb) signalling pathway (THBS1, TGFb2, TGFb R1 & TGFb R2) were consistently down-regulated in the post-selection HMEC population. Gene suppression was not associated with DNA methylation but was associated with chromatin remodelling, involving a decrease in histone H3 lysine 27 (H3K27) tri-methylation and an increase in histone H3 lysine 9 (H3K9) di-methylation and H3K9 de-acetylation. Similar epigenetic repression was also identified MDAMB453 breast cancer cells and in breast tumour samples. These results demonstrate for the first time that TGFb2, its receptors TGFb R1 & TGFb R2 and activator THBS1 are concordantly suppressed early in breast carcinogenesis by repressive histone modifications and indicate that the TGFb signalling pathway is a novel target for gene activation by epigenetic therapy. Keywords: cell differentiation, breast cancer, gene silencing, epigenetics Two-colour reference design was used. Two biological replicates were included in the study - Bre60 and Bre-80. Each cell line was sampled at pre-selection stage, post-selection stage and post AZA treatment. The post-selection stage was chosen as the reference sample, and a control post-post hybridisation included to assess variability across the assay.

Project description:Breast cancer (BC) is one of the leading causes of cancer-related deaths in women. The purpose of this study is to identify key molecular markers related to the diagnosis and prognosis of early breast cancer (EBC). The data of mRNA, lncRNA and DNA methylation were downloaded from The Cancer Genome Atlas (TCGA) dataset for identification of differentially expressed mRNAs (DEmRNAs), differentially expressed lncRNAs (DElncRNAs) and DNA methylation analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyzes were used to identify the biological functions of DEmRNAs. The correlation analysis between DNA methylation and DEmRNAs was carried out. Then, diagnostic analysis and prognostic analysis of identified DEmRNAs and DElncRNAs were also performed in the TCGA database. Subsequently, methylation state verification for identified DEmRNAs was performed in the GSE32393 dataset. In addition, real-time polymerase chain reaction (RT-PCR) in vitro verification of genes was performed. Finally, AC093110.1 was overexpressed in human BC cell line MCF-7 to verify cell proliferation and migration. In this study, a total of 1633 DEmRNAs, 750 DElncRNAs and 8042 differentially methylated sites were obtained, respectively. In the Venn analysis, 11 keys DEmRNAs (ALDH1L1, SPTBN1, MRGPRF, CAV2, HSPB6, PITX1, WDR86, PENK, CACNA1H, ALDH1A2 and MME) were we found. ALDH1A2, ALDH1L1, HSPB6, MME, MRGPRF, PENK, PITX1, SPTBN1, WDR86 and CAV2 may be considered as potential diagnostic gene biomarkers in EBC. Strikingly, CAV2, MME, AC093110.1 and AC120498.6 were significantly actively correlated with survival. Methylation state of identified DEmRNAs in GSE32393 dataset was consistent with the result in TCGA. AC093110.1 can affect the proliferation and migration of MCF-7. ALDH1A2, ALDH1L1, HSPB6, MME, MRGPRF, PENK, PITX1, SPTBN1, WDR86 and CAV2 may be potential diagnostic gene biomarkers of EBC. Strikingly, CAV2, MME, AC093110.1 and AC120498.6 were significantly actively correlated with survival. The identification of these genes can help in the early diagnosis and treatment of EBC. In addition, AC093110.1 can regulate SPTBN1 expression and play an important role in cell proliferation and migration, which provides clues to clarify the regulatory mechanism of EBC.

Dataset Information

Methylation of homeobox genes is a frequent and early epigenetic event in breast cancer.

Publications

Methylation of homeobox genes is a frequent and early epigenetic event in breast cancer.

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