Epigenetic control of cellular plasticity in breast cancer progression

Breast cancer remains a leading cause of death among women, with the majority of mortality being attributed to metastatic disease and acquisition of therapeutic resistance. Epigenetic-driven plasticity in breast cancer cells is a critical mediator of breast cancer progression and remains a leading challenge for effective treatment. Broadly, we categorize breast cancer plasticity into four interconnected processes: (a) development of cancer stem cell traits, (b) epithelial-to-mesenchymal transition (EMT), (c) luminal-to-basal lineage switching, and (d) acquisition of therapeutic resistance and recurrence. Here, we first assess the evidence supporting the cell of origin for breast cancer subtypes, which are directly influenced by distinct chromatin landscapes, and can impact cellular state during breast cancer initiation. Then, we highlight well-documented epigenetic regulatory mechanisms and associated epigenetic regulators which can dictate these four processes to drive breast cancer plasticity. In particular, we discuss recent evidence that epigenetic therapies, or epidrugs, can induce basal-to-luminal switching, termed redifferentiation. This approach can be exploited to restore therapeutic sensitivity in basal-like and aggressive HER2-driven breast cancers, therefore presenting as viable strategies in combination with standard of care therapeutics. We conclude with anticipated future directions in targeting cell plasticity as a therapeutic strategy and offer new opportunities for drug development.