Mahendran Gowthami, Shangaradas Ann Dharshika, Romero-Moreno Ricardo, Wickramarachchige Dona Nadeeshika, Sarasija S H G Sumudu, Perera Sumeth, Silva Gayathri N
Department of Chemistry, Faculty of Science, University of Colombo, Colombo, Sri Lanka.
Harper Cancer Research Institute, South Bend, IN, United States.
Front Oncol. 2024 Dec 18;14:1499950. doi: 10.3389/fonc.2024.1499950. eCollection 2024.
Triple-negative breast cancer (TNBC) is a highly aggressive and clinically challenging subtype of breast cancer, lacking the expression of estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. The absence of these receptors limits therapeutic options necessitating the exploration of novel treatment strategies. Epigenetic modifications, which include DNA methylation, histone modifications, and microRNA (miRNA) regulation, play a pivotal role in TNBC pathogenesis and represent promising therapeutic targets. This review delves into the therapeutic potential of epigenetic interventions in TNBC, with a focus on DNA methylation, histone modifications, and miRNA therapeutics. We examine the role of DNA methylation in gene silencing within TNBC and the development of DNA methylation inhibitors designed to reactivate silenced tumor suppressor genes. Histone modifications, through histone deacetylation and acetylation in particular, are critical in regulating gene expression. We explore the efficacy of histone deacetylase inhibitors (HDACi), which have shown promise in reversing aberrant histone deacetylation patterns, thereby restoring normal gene function, and suppressing tumor growth. Furthermore, the review highlights the dual role of miRNAs in TNBC as both oncogenes and tumor suppressors and discusses the therapeutic potential of miRNA mimics and inhibitors in modulating these regulatory molecules to inhibit cancer progression. By integrating these epigenetic therapies, we propose a multifaceted approach to target the underlying epigenetic mechanisms that drive TNBC progression. The synergistic use of DNA methylation inhibitors, HDACi, and the miRNA-based therapies offers a promising avenue for personalized treatment strategies, aiming to enhance the clinical outcome for patients with TNBC.
三阴性乳腺癌（TNBC）是一种极具侵袭性且在临床上具有挑战性的乳腺癌亚型，缺乏雌激素受体（ER）、孕激素受体（PR）和HER2/neu的表达。这些受体的缺失限制了治疗选择，因此需要探索新的治疗策略。表观遗传修饰，包括DNA甲基化、组蛋白修饰和微小RNA（miRNA）调控，在TNBC发病机制中起关键作用，并代表了有前景的治疗靶点。本综述深入探讨了表观遗传干预在TNBC中的治疗潜力，重点关注DNA甲基化、组蛋白修饰和miRNA治疗。我们研究了DNA甲基化在TNBC基因沉默中的作用以及旨在重新激活沉默的肿瘤抑制基因的DNA甲基化抑制剂的开发。组蛋白修饰，特别是通过组蛋白去乙酰化和乙酰化，在调节基因表达中至关重要。我们探讨了组蛋白去乙酰化酶抑制剂（HDACi）的疗效，这些抑制剂在逆转异常的组蛋白去乙酰化模式、从而恢复正常基因功能和抑制肿瘤生长方面已显示出前景。此外，该综述强调了miRNA在TNBC中作为癌基因和肿瘤抑制基因的双重作用，并讨论了miRNA模拟物和抑制剂在调节这些调控分子以抑制癌症进展方面的治疗潜力。通过整合这些表观遗传疗法，我们提出了一种多方面的方法来靶向驱动TNBC进展的潜在表观遗传机制。DNA甲基化抑制剂、HDACi和基于miRNA的疗法的协同使用为个性化治疗策略提供了一条有前景的途径，旨在改善TNBC患者的临床结局。
