Coordinated epigenetic remodelling of transcriptional networks occurs during early breast carcinogenesis

Clinical Epigenetics

Susan J Clark⁵  Lily I Huschtscha¹  Roger R Reddel⁴  Andrew Stone⁵  Rebecca A Hinshelwood³  Mark D Robinson²  Clare Stirzaker⁵  Elena Zotenko⁵  Warwick J Locke⁵ 

[1] Cancer Research Unit, Children’s Medical Research Institute, 2145 Hawkesbury Road, Westmead 2145, NSW, Australia;Swiss Institute of Bioinformatics, University of Zurich, Zurich, and Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland;Sydney West Cancer Trials Centre, Crown Princess Mary Cancer Centre Westmead, Westmead Hospital, Hawkesbury Road, Westmead 2145, NSW, Australia;Sydney Medical School, University of Sydney, Fisher Road, Sydney 2006, NSW, Australia;St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Level 5 deLacy Building, St Vincent’s Hospital, Victoria Street, Darlinghurst 2010, NSW, Australia

关键词: Biomarker;    Epigenome sequencing;    Basal breast cancer;    Epigenetics;    Methylome;    DNA methylation;   

Others  :  1206097
DOI  :  10.1186/s13148-015-0086-0

 received in 2014-11-24, accepted in 2015-04-16,  发布年份 2015

【 摘 要 】

Background

Dysregulation of the epigenome is a common event in malignancy; however, deciphering the earliest cancer-associated epigenetic events remains a challenge. Cancer epigenome studies to date have primarily utilised cancer cell lines or clinical samples, where it is difficult to identify the initial epigenetic lesions from those that occur over time. Here, we analysed the epigenome of human mammary epithelial cells (HMEC) and a matched variant cell population (vHMEC) that have spontaneously escaped senescence and undergone partial carcinogenic transformation. Using this model of basal-like breast carcinogenesis, we provide striking new insights into the very first epigenetic changes that occur during the initial stages of malignancy.

Results

The first phase of malignancy is defined by coordinated changes in the epigenome. At the chromatin level, this is embodied in long-range epigenetic deregulation, which involves the concomitant but atypical acquisition or loss of active and repressive histone modifications across large regional blocks. Changes in DNA methylation also occurs in a highly coordinated manner. We identified differentially methylated regions (DMRs) in the very earliest passages of vHMECs. Notably, we find that differential methylation targets loci regulated by key transcription factors including p53, AHR and E2F family members suggesting that epigenetic deregulation of transcription factor binding is a key event in breast carcinogenesis. Interestingly, DMRs identified in vHMEC are extensively methylated in breast cancer, with hypermethylation frequently encroaching into neighbouring regions. A subset of vHMEC DMRs exhibited a strong basal-like cancer specific hypermethylation.

Conclusions

Here, we generated epigenome-wide maps of the earliest phase of breast malignancy and show long-range epigenetic deregulation and coordinated DNA hypermethylation targets loci regulated by key transcription factors. These findings support a model where induction of breast cancer occurs through epigenetic disruption of transcription factor binding leading to deregulation of cancer-associated transcriptional networks. With their stability and very early occurrence, vHMECs hypermethylated loci could serve as excellent biomarkers for the initial detection of basal breast cancer.

【 授权许可】

   
2015 Locke et al.; licensee BioMed Central.

【 图 表 】

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