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

• Abstract: INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
• Authors: Stella Tommasi, Deborah L Karm, Xiwei Wu, Yun Yen, Gerd P Pfeifer (Affiliation: Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. stommasi at coh.org)
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 11 Issue 1 Pg. R14 ( 2009) ISSN: 1465-542X [Electronic] England
• PMID: 19250546 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Homeodomain Proteins

Topics

• Breast Neoplasms (genetics, pathology)
• Carcinoma, Ductal, Breast (genetics, secondary)
• CpG Islands
• DNA Methylation
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Genome, Human
• Homeodomain Proteins (genetics)
• Humans
• Oligonucleotide Array Sequence Analysis
• Prognosis
• Promoter Regions, Genetic (genetics)