Abstract
BackgroundDysregulation 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.ResultsThe 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.ConclusionsHere, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0086-0) contains supplementary material, which is available to authorized users.
Highlights
Dysregulation of the epigenome is a common event in malignancy; deciphering the earliest cancer-associated epigenetic events remains a challenge
Comparison to The Cancer Genome Atlas BReast invasive CArcinoma (TCGA-BRCA) cohort demonstrates that the methylation aberrations we identified in variant HMEC (vHMEC) are common in basal-like breast tumours suggesting that epigenetic lesions occurring early in carcinogenesis are derived by similar reprogramming events
Results vHMEC is a model of early basal-like breast carcinogenesis To gain a more detailed understanding of the early epigenetic changes that occur in the first stages of carcinogenesis, we performed epigenome-wide profiling of four isogenic human mammary epithelial cells (HMEC)/vHMEC lines (Bre12, Bre38, Bre67 and Bre98)
Summary
Dysregulation of the epigenome is a common event in malignancy; deciphering the earliest cancer-associated epigenetic events remains a challenge. 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. When compared to HMECs, vHMECs exhibit multiple cancer-associated gene expression and epigenetic changes and are considered to represent a partially transformed pre-malignant breast cell (reviewed in Locke and Clark [10] and Hinshelwood and Clark [13]). The HMEC system is an ideal tool for the identification of the first epigenomic events occurring during early breast carcinogenesis
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