Emerging Role of Epigenetic Modifiers in Breast Cancer Pathogenesis and Therapeutic Response

Simple Summary Worldwide, breast cancer is among the most frequently diagnosed cancers in women and the second leading cause of cancer-associated mortality in women. While tumor genetics contribute to therapies used to treat breast cancer and inform patient prognosis, modifications of histone proteins, which help organize the genetic material in cells into chromatin, can also influence therapeutic response and ultimately patient outcome. Here, we explore the role of enzymes that modify histone proteins in breast cancer. We discuss how these reversible, or "epigenetic", changes to chromatin perturb the tumor environment and describe preclinical studies that provide a rationale for targeting chromatin-modifying enzymes in breast cancer. We build on existing preclinical data to connect epigenetic activity with changes in cells that support oncogenic growth and, when applicable, assess the current clinical status of treatments that target chromatin-modifying enzymes in breast cancer. Breast cancer pathogenesis, treatment, and patient outcomes are shaped by tumor-intrinsic genomic alterations that divide breast tumors into molecular subtypes. These molecular subtypes often dictate viable therapeutic interventions and, ultimately, patient outcomes. However, heterogeneity in therapeutic response may be a result of underlying epigenetic features that may further stratify breast cancer patient outcomes. In this review, we examine non-genetic mechanisms that drive functional changes to chromatin in breast cancer to contribute to cell and tumor fitness and highlight how epigenetic activity may inform the therapeutic response. We conclude by providing perspectives on the future of therapeutic targeting of epigenetic enzymes, an approach that holds untapped potential to improve breast cancer patient outcomes.