Chatterjee Prarthana, Banerjee Satarupa
School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
Sci Rep. 2025 Jan 6;15(1):964. doi: 10.1038/s41598-024-85100-w.
The proliferation-specific oncogenic transcription factor, FOXM1 is overexpressed in primary and recurrent breast tumors across all breast cancer (BC) subtypes. Intriguingly, FOXM1 overexpression was found to be highest in Triple-negative breast cancer (TNBC), the most aggressive BC with the worst prognosis. However, FOXM1-mediated TNBC pathogenesis is not completely elucidated. Single nucleotide polymorphisms (SNPs) are the most common genetic variations causing functional and structural aberrations in proteins enhancing cancer susceptibility. This computational investigation attempted to identify the malignant FOXM1 non-synonymous SNPs (nsSNPs) and evaluate their role in affecting the conformational and functional stability, evolutionary conservation, post-translational modifications, and malignant susceptibility of the protein. Out of a huge data pool of 8826 FOXM1 SNPs using several in-silico sequence-based tools and structural approaches, four SNPs viz. E235Q, R256C, G429E and S756P were identified as pathogenic nsSNPs and among the shortlisted variants molecular dynamics simulations identified E235Q as the most damaging malignant SNP, followed by S756P. Additionally, the defective drug and DNA binding motif of E235Q and S756P were also determined in our study. Thus, although further in-vitro validations are awaited the findings of this in-silico work can be used as a blueprint for malignant nsSNP identification of FOXM1 aiding in clinical TNBC therapeutics.
增殖特异性致癌转录因子FOXM1在所有乳腺癌（BC）亚型的原发性和复发性乳腺肿瘤中均过度表达。有趣的是，FOXM1的过度表达在三阴性乳腺癌（TNBC）中最高，TNBC是最具侵袭性且预后最差的乳腺癌。然而，FOXM1介导的TNBC发病机制尚未完全阐明。单核苷酸多态性（SNP）是导致蛋白质功能和结构异常从而增强癌症易感性的最常见基因变异。这项计算研究试图识别恶性的FOXM1非同义SNP（nsSNP），并评估它们在影响蛋白质的构象和功能稳定性、进化保守性、翻译后修饰以及恶性易感性方面的作用。使用多种基于计算机序列的工具和结构方法，在8826个FOXM1 SNP的庞大数据库中，识别出四个SNP，即E235Q、R256C、G429E和S756P为致病性nsSNP，在入围的变异中，分子动力学模拟确定E235Q是最具破坏性的恶性SNP，其次是S756P。此外，我们的研究还确定了E235Q和S756P的缺陷药物和DNA结合基序。因此，尽管有待进一步的体外验证，但这项计算机研究的结果可作为FOXM1恶性nsSNP鉴定的蓝图，有助于临床TNBC治疗。
