Epigenetic Mechanisms Influencing Therapeutic Response in Breast Cancer

Abstract

The majority of breast cancers are estrogen receptor (ER)+ and agents targeting the ER signaling pathway have markedly increased survival for women with breast cancer for decades. However, therapeutic resistance eventually emerges, especially in the metastatic setting. In the past decade disrupted epigenetic regulatory processes have emerged as major contributors to carcinogenesis in many cancer types. Aberrations in chromatin modifiers and transcription factors have also been recognized as mediators of breast cancer development and therapeutic outcome, and new epigenetic-based therapies in combination with targeted therapies have been proposed. Here we will discuss recent progress in our understanding of the chromatin-based mechanisms of breast tumorigenesis, how these mechanisms affect therapeutic response to standard of care treatment, and discuss new strategies towards therapeutic intervention to overcome resistance.

Current Advances in Breast Cancer: Implications for Developing New Treatment Strategies Through Epi-Drugs on the Road to Modifying the Epigenome

“…Although the therapeutic efficacy of these drugs has been tested in various clinical phase studies, current treatment approaches focus more on the rationale and combinatorial use of these epi-drugs to demonstrate their synergistic effects and reduce the side effects caused by current chemotherapeutic agents. 36 For instance, the suppression of EZH2, along with the antiproliferative effect of resveratrol, one of the polyphenols and an important component of the Mediterranean Diet, attracts attention in terms of providing this synergistic effect. Additionally, due to its natural compound properties, it holds the potential to eliminate potential side effects during treatment.…”

“…Considering the examples of combinatorial treatment strategies in estrogen receptor-positive (ER + ) breast cancer, an improvement in the clinical benefit rate was observed in phase II clinical trials (NCT00676663 and NCT00828854) with the co-administration of exemestane (an aromatase inhibitor) and Entinostat (an HDACi). 36 In addition, another ongoing clinical trial (NCT04315233) aims to examine the tolerance level of ribociclib, a Cyclin Dependent Kinase (CDK4/6) inhibitor, and Belinostat (another HDAC inhibitor) in inhibiting cell line growth in patients diagnosed with metastatic TNBC. Trichostatin A (TSA), which keeps the cell cycle in the G1 and G2 phases and has a strong effect on tumor growth inhibition, is considered among the leading epi-drugs categorized under hydroxamic acids in this regard.…”

Balance Cell Apoptosis and Pyroptosis of Caspase-3-Activating Chemotherapy for Better Antitumor Therapy

“…They regulate gene activity without changing the DNA sequence, and participate in the regulation of gene expression, playing a key role in cell proliferation and cell differentiation. However, their abnormal expression may induce the development of various malignant tumors and tumor drug resistances [50]. Therefore, targeting epigenetic alterations may inhibit tumorigenesis and drug resistance.…”