Centre for Drug Research, Universiti Sains Malaysia, USM, 11800 Pulau Pinang, Malaysia; Department of Chemistry and Industrial Chemistry, Kwara State University, P.M.B., Malete, 1530 Ilorin, Nigeria.
Department of Chemistry and Industrial Chemistry, Kwara State University, P.M.B., Malete, 1530 Ilorin, Nigeria.
Biochim Biophys Acta Gene Regul Mech. 2022 Oct;1865(7):194873. doi: 10.1016/j.bbagrm.2022.194873. Epub 2022 Sep 5.
Breast cancer remains one of the leading causes of cancer-related deaths globally and the most prominent among females, yet with limited effective therapeutic options. Most of the current medications are challenged by various factors including low efficacy, incessant resistance, immune evasion and frequent recurrence of the disease. Further understanding of the prognosis and identification of plausible therapeutic channels thus requires multimodal approaches. In this review, epigenetics studies of several pathways to BC oncogenesis via the inducement of oncogenic changes on relevant markers have been overviewed. Similarly, the counter-epigenetic mechanisms to reverse such changes as effective therapeutic strategies were surveyed. The epigenetic oncogenesis occurs through several pathways, notably, DNMT-mediated hypermethylation of DNA, dysregulated expression for ERα, HER2/ERBB and PR, histone modification, overexpression of transcription factors including the CDK9-cyclin T1 complex and suppression of tumour suppressor genes. Scientifically, the regulatory reversal of the mechanisms constitutes effective epigenetic approaches for mitigating BC initiation, progression and metastasis. These were exhibited at various experimental levels by classical chemotherapeutic agents including some repurposable drugs, endocrine inhibitors, monoclonal antibodies and miRNAs, natural products, metal complexes and nanoparticles. Dozens of the potential candidates are currently in clinical trials while others are still at preclinical experimental stages showing promising anti-BC efficacy. The review presents a model for a wider understanding of epigenetic oncogenic pathways to BC and reveals plausible channels for reversing the unpleasant changes through epigenetic modifications. It advances the science of therapeutic designs for ameliorating the global burden of BC upon further translational studies.
乳腺癌仍然是全球癌症相关死亡的主要原因之一，也是女性中最常见的癌症，但有效的治疗选择有限。大多数现有的药物都受到各种因素的挑战，包括疗效低、持续耐药、免疫逃避和疾病频繁复发。因此，进一步了解预后并确定合理的治疗途径需要采用多模式方法。在这篇综述中，概述了通过诱导相关标志物的致癌变化来研究乳腺癌发生的几种途径的表观遗传学研究。同样，调查了逆转这些变化的反表观遗传机制作为有效的治疗策略。表观遗传致癌作用通过几种途径发生，特别是 DNA 的 DNMT 介导的过度甲基化、ERα、HER2/ERBB 和 PR 的表达失调、组蛋白修饰、包括 CDK9-cyclin T1 复合物在内的转录因子的过表达以及肿瘤抑制基因的抑制。从科学上讲，这些机制的调控逆转构成了减轻乳腺癌发生、进展和转移的有效表观遗传方法。这些方法在各种实验水平上都得到了展示，包括经典的化疗药物，如一些重新利用的药物、内分泌抑制剂、单克隆抗体和 miRNAs、天然产物、金属配合物和纳米粒子。目前有数十种潜在的候选药物正在临床试验中，而其他药物仍处于临床前实验阶段，显示出有希望的抗乳腺癌疗效。该综述提供了一个更广泛地了解乳腺癌表观遗传致癌途径的模型，并揭示了通过表观遗传修饰逆转不愉快变化的可能途径。它通过进一步的转化研究，推进了改善全球乳腺癌负担的治疗设计科学。
