Advances in the epigenetic regulation of breast cancer

The clonal evolution of breast cancer involves a complex dialogue between tumor cells and their environment. In this process, epigenetic mechanisms play a crucial role in regulating the cellular transcriptome without altering the underlying DNA sequence. Here, we provide an updated summary of three main epigenetic mechanisms: histone modifications, long non-coding RNAs (lncRNAs), and higher-order chromatin structures. Post-translational modifications of DNA or histones influence gene expression by altering chromatin accessibility and/or recruiting regulatory protein complexes. This process is dynamically regulated by enzymes that add or remove these marks, as well as by reader proteins that recognize them. Dysregulated expression or malfunction of these regulators creates an aberrant epigenetic landscape and gene expression profile, contributing to breast cancer initiation, metastasis, and drug resistance. Notably, the donor molecules for chromatin modifications are largely derived from intermediate metabolites shaped by environmental cues, highlighting the intricate crosstalk between epigenetic regulation and both cellular and systemic metabolic states. DNA and histone modifications are further interrelated with lncRNAs and higher-order chromatin architectures, which have been actively investigated in breast carcinogenesis. We also briefly introduce the role of epigenetics in other chromatin-associated events such as replication initiation. Aberrant replication initiation can drive gene duplication and genomic alterations resembling those observed in clinical breast cancer, endowing tumor cells with growth advantages and therapeutic resistance. Finally, we summarize emerging therapeutic strategies that target epigenetic vulnerabilities in breast cancer and discuss their current limitations and future directions.