Mehraj Umar, Qayoom Hina, Shafi Shazia, Farhana Pzd, Asdaq Syed Mohammed Basheeruddin, Mir Manzoor Ahmad
Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, J&K India.
Department of Pharmacy Practice, College of Pharmacy, Almaarefa University, Riyadh 13713, KSA.
Anticancer Agents Med Chem. 2022;22(17):3025-3037. doi: 10.2174/1871520622666220419135547.
DNA Topoisomerase II Alpha (TOP2A), a protein-coding gene, is central to the replication process and has been found deregulated in several malignancies, including breast cancer. Several therapeutic regimens have been developed and approved for targeting TOP2A and have prolonged the survival of cancer patients. However, due to the inherent nature of the tumor cell to evolve, the earlier positive response turns into a refractory chemoresistance in breast cancer patients.
The study's main objective was to analyze the expression pattern and prognostic significance of TOP2A in breast cancer patients and screen new therapeutic molecules targeting TOP2A.
We utilized an integrated bioinformatic approach to analyze the expression pattern, genetic alteration, immune association, and prognostic significance of TOP2A in breast cancer (BC) and screened natural compounds targeting TOP2A, and performed an in silico and an in vitro analysis.
Our study showed that TOP2A is highly overexpressed in breast cancer tissues and overexpression of TOP2A correlates with worse overall survival (OS) and relapse-free survival (RFS). Moreover, TOP2A showed a high association with tumor stroma, particularly with myeloid-derived suppressor cells. Also, in silico and in vitro analysis revealed cryptolepine as a promising natural compound targeting TOP2A.
Cumulatively, this study signifies that TOP2A promotes breast cancer progression, and targeting TOP2A in combination with other therapeutic agents will significantly enhance the response of BC patients to therapy and reduce the development of chemoresistance.
DNA拓扑异构酶IIα（TOP2A）是一种蛋白质编码基因，对复制过程至关重要，并且已发现在包括乳腺癌在内的多种恶性肿瘤中其表达失调。已经开发并批准了几种针对TOP2A的治疗方案，这些方案延长了癌症患者的生存期。然而，由于肿瘤细胞进化的固有特性，早期的阳性反应在乳腺癌患者中会转变为难治性化疗耐药。
本研究的主要目的是分析TOP2A在乳腺癌患者中的表达模式和预后意义，并筛选针对TOP2A的新治疗分子。
我们采用综合生物信息学方法分析TOP2A在乳腺癌（BC）中的表达模式、基因改变、免疫关联和预后意义，筛选针对TOP2A的天然化合物，并进行了计算机模拟和体外分析。
我们的研究表明，TOP2A在乳腺癌组织中高度过表达，TOP2A的过表达与较差的总生存期（OS）和无复发生存期（RFS）相关。此外，TOP2A与肿瘤基质高度相关，特别是与髓源性抑制细胞相关。此外，计算机模拟和体外分析显示隐丹参酮是一种有前景的针对TOP2A的天然化合物。
总体而言，本研究表明TOP2A促进乳腺癌进展，将TOP2A与其他治疗药物联合靶向治疗将显著增强BC患者对治疗的反应并减少化疗耐药的发生。
