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

Abstract

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.

Keywords: HAT; HDAC; breast cancer; chromatin modification; epigenetics; histone acetylation; histone methylation.

Figure 2

Functional mechanisms of the clinically viable HDAC inhibitors. (a) Vorinostat inhibits HDAC activity, resulting in the accumulation of hyperacetylated histones H3 and H4, leading to the transcriptional activation of genes including TBP-2 and p21^WAF1 [161,162]. The induced activation of p21^WAF1 supports G1 cell cycle arrest followed by apoptosis. (b) Romidepsin inhibits cellular proliferation via the accumulation of hyperacetylated histones, resulting in replication fork delays and DNA double-strand break formation [163]. Thus, romidepsin-driven DNA damage induces cell cycle arrest and apoptosis. Romidepsin also inhibits the PI3K pathway, a master regulator of cell metabolism, growth, proliferation, and survival [164]. (c) HDAC inhibition via belinostat leads to PKA-dependent downregulation and degradation of survivin, mediating cell death [165]. Additionally, belinostat induces TIMP-1 expression, which may decrease tumor cell invasion and inhibit metastasis [166]. (d) The HDAC inhibitor panobinostat synergizes with the proteasome inhibitor bortezomib to block the proteasomal degradation and aggresome accumulation of ubiquitinated misfolded proteins. Ubiquitinated proteins are normally transported via HDAC6 association and the dynein motor for aggresome processing. HDAC inhibition via panobinostat results in the accumulation of misfolded proteins, inducing endoplasmic reticulum (ER) stress, and ultimately, cell death [167,168]. (e) Entinostat activates the transcription of immune response genes such as IFNG, CD274 (PD-L1), and genes encoding MHC proteins, which support immune activation and increase antigen presentation on tumor cells [169,170]. (f) Tucidinostat increases T cell-attracting chemokines, including CCL5, enhancing T cell intra-tumoral infiltration. Tucidinostat also modulates the M1 polarization of macrophages in solid tumors [171].

Figure 1

Epigenetic regulation of histone acetylation and deacetylation. HATs and HDACs have a crucial role in gene regulation. These enzymes are responsible for the transfer and removal of acetyl groups from lysine residues in histones. HDACs are classified into class I (HDAC 1, 2, 3, and 8), class II (HDAC 4, 5, 6, 7, 9, and 10), class III (SIRT1-7), and class IV (HDAC 11). HAT-directed lysine acetylation on histones promotes an open chromatin structure that enhances transcriptional competence. HDAC-directed lysine deacetylation supports chromatin compaction, thereby reducing transcriptional activity. Dysregulation of these chromatin-modifying enzymes aids in aberrant cellular proliferation, angiogenesis, epithelial-to-mesenchymal transition, and escape from cell cycle arrest and evasion of apoptosis. While HAT inhibition remains in preclinical development, four HDAC inhibitors are currently FDA-approved for human cancers and are denoted by *.