Abstract
Epigenetic gene regulation has influence over a diverse range of cellular functions, including the maintenance of pluripotency, differentiation, and cellular identity, and is deregulated in many diseases, including cancer. Whereas the involvement of epigenetic dysregulation in cancer is well documented, much of the mechanistic detail involved in triggering these changes remains unclear. In the current age of genomics, the development of new sequencing technologies has seen an influx of genomic and epigenomic data and drastic improvements in both resolution and coverage. Studies in cancer cell lines and clinical samples using next-generation sequencing are rapidly delivering spectacular insights into the nature of the cancer genome and epigenome. Despite these improvements in technology, the timing and relationship between genetic and epigenetic changes that occur during the process of carcinogenesis are still unclear. In particular, what changes to the epigenome are playing a driving role during carcinogenesis and what influence the temporal nature of these changes has on cancer progression are not known. Understanding the early epigenetic changes driving breast cancer has the exciting potential to provide a novel set of therapeutic targets or early-disease biomarkers or both. Therefore, it is important to find novel systems that permit the study of initial epigenetic events that potentially occur during the first stages of breast cancer. Non-malignant human mammary epithelial cells (HMECs) provide an exciting in vitro model of very early breast carcinogenesis. When grown in culture, HMECs are able to temporarily escape senescence and acquire a pre-malignant breast cancer-like phenotype (variant HMECs, or vHMECs). Cultured HMECs are composed mainly of cells from the basal breast epithelial layer. Therefore, vHMECs are considered to represent the basal-like subtype of breast cancer. The transition from HMECs to vHMECs in culture recapitulates the epigenomic phenomena that occur during the progression from normal breast to pre-malignancy. Therefore, the HMEC model system provides the unique opportunity to study the very earliest epigenomic aberrations occurring during breast carcinogenesis and can give insight into the sequence of epigenomic events that lead to breast malignancy. This review provides an overview of epigenomic research in breast cancer and discusses in detail the utility of the HMEC model system to discover early epigenomic changes involved in breast carcinogenesis.
Highlights
Epigenetics is defined as a heritable change in phenotype without a change to the underlying DNA sequence
This review aims to integrate some of the recent findings of epigenomic research in cancer and will cover in detail an under-used but powerful model of early breast carcinogenesis: human mammary epithelial cells (HMECs)
The results showed that a significant increase in DNA methylation levels of promoter cytosine followed by guanosine dinucleotide (CpG) islands occurred between normal breast (NB) and atypical ductal hyperplasia (ADH)/flat epithelial atypia (FEA)
Summary
Epigenetics is defined as a heritable change in phenotype without a change to the underlying DNA sequence. Temporal changes in DNA methylation occur as variant human mammary epithelial cells escape senescence Despite the demonstrated stability of the vHMEC methylome [123], there is significant heterogeneity in methylation patterns across the p16ink4a promoter as determined by bisulphite sequencing Some regions at this site appear to be protected from hypermethylation during gene silencing [103]. The implantation of HMECs into mouse mammary fat pads humanized with fibroblasts transformed to abnormally express key growth factors resulted in the generation of structures similar to those seen in early breast malignancy [124] These results demonstrate that the HMEC system is a useful model for studies of the role of cancer/stroma interactions during carcinogenesis. The development of further model systems using HMECs and vHMECs that follow the natural progression of cancer growth in vivo will be invaluable to the understanding of breast cancer biology
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