{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T01:21:24Z","timestamp":1771464084071,"version":"3.50.1"},"reference-count":101,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T00:00:00Z","timestamp":1671753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In peripheral blood, cell\u2010free DNA (cfDNA) contains circulating tumor DNA (ctDNA), which indicates molecular abnormalities in metastatic breast tumor tissue. The sequencing of cfDNA of Metastatic Breast Cancer (MBC) patients allows assessment of therapy response and noninvasive treatment. In the proposed study, clinically significant alterations in <jats:italic>PIK3CA<\/jats:italic> and <jats:italic>TP53<\/jats:italic> genes associated with MBC resulting in a missense substitution of His1047Arg and Arg282Trp from an next\u2010generation sequencing\u2010based multi\u2010gene panel were reported in a cfDNA of a patient with MBC. To investigate the impact of the reported mutation, we used molecular docking, molecular dynamics simulation, network analysis, and pathway analysis. Molecular Docking analysis determined the distinct binding pattern revealing H1047R\u2010ATP complex has a higher number of Hydrogen bonds (H\u2010bonds) and binding affinity with a slight difference compared to the PIK3CA\u2010ATP complex. Following, molecular dynamics simulation for 200\u2009ns, of which H1047R\u2010ATP complex resulted in the instability of PIK3CA. Similarly, for TP53 mutant R282W, the zinc\u2010free state (apo) and zinc\u2010bounded (holo) complexes were investigated for conformational change between apo and holo complexes, of which the holo complex mutant R282W was unstable. To validate the conformational change of PIK3CA and TP53, 80% mutation of H1047R in the kinase domain of p110\u03b1 expressed ubiquitously in PIK3CA protein that alters PI3K pathway, while R282W mutation in DNA binding helix (H2) region of P53 protein inhibits the transcription factor in P53 pathway causing MBC. According to our findings, the extrinsic (hypoxia, oxidative stress, and acidosis); intrinsic factors (<jats:italic>MYC<\/jats:italic> amplification) in PIK3CA and TP53 mutations will provide potential insights for developing novel therapeutic methods for MBC therapy.<\/jats:p>","DOI":"10.1002\/jcb.30354","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T17:05:11Z","timestamp":1671815111000},"page":"188-204","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["An integrated investigation of structural and pathway alteration caused by PIK3CA and TP53 mutations identified in cfDNA of metastatic breast cancer"],"prefix":"10.1002","volume":"124","author":[{"given":"Hephzibah Cathryn","family":"R.","sequence":"first","affiliation":[{"name":"Laboratory of Integrative Genomics, Department of Integrative Biology School of Bio Sciences and Technology, Vellore Institute of Technology  Vellore Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6639-3746","authenticated-orcid":false,"given":"Udhaya","family":"Kumar S.","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Genomics, Department of Integrative Biology School of Bio Sciences and Technology, Vellore Institute of Technology  Vellore Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gnanasambandan","family":"R.","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Genomics, Department of Integrative Biology School of Bio Sciences and Technology, Vellore Institute of Technology  Vellore Tamil Nadu India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. 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