{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T02:51:37Z","timestamp":1781751097907,"version":"3.54.5"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":49,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Wu jieping Medicine Prize","award":["grant number 320.6750.2023-11-10"],"award-info":[{"award-number":["grant number 320.6750.2023-11-10"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Discov Onc"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pyrimidine metabolism plays a crucial role in DNA synthesis and cell proliferation and is associated with the development of various cancers. However, their prognostic value in triple-negative breast cancer remains to be further investigated. This study aimed to identify the prognostic genes related to pyrimidine metabolism in triple-negative breast cancer (TNBC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>All data applied in this study were obtained from public databases. The prognostic genes related to pyrimidine metabolism in TNBC were identified through Weighted gene co-expression network analysis (WGCNA), differential expression analysis, univariate Cox regression, and 101 combinations of machine learning algorithms. Based on the optimal model among the 101 combinations of machine learning algorithms, a risk model was built. Then, the risk model was validated in GSE58812 dataset. Subsequently, a nomogram was built based on prognostic genes. Meanwhile, enrichment analysis, gene mutation analysis, and drug sensitivity analysis were also executed. In addition, the somatic mutation analysis of TNBC patients revealed that missense mutations were the predominant mutation type. To explore the cells that influence the risk of TNBC, single-cell RNA sequencing analysis was conducted. Finally, the expression levels of prognostic genes were verified through qPCR experiments. SEPT3 expression in TNBC cells was detected by qPCR; its effects on TNBC cell proliferation (CCK-8) and invasion\/migration (Transwell, wound-healing) were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Firstly, 5 prognostic genes (ECE2, NFE2L3, PFKFB3, FADS2, and SEPT3) were identified. The risk model demonstrated high reliability, and the survival rate of high-risk patients was relatively low. A nomogram with relatively high prognostic accuracy was constructed. Next, 22 pathways were identified by enrichment analysis. A drug sensitivity analysis identified 12 drugs were identified (e.g. ABT.263). In addition, epithelial cells were related to the expression of the prognostic genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>ECE2, NFE2L3, PFKFB3, FADS2, and SEPT3 are associated with pyrimidine metabolism in TNBC. A risk model and nomogram were successfully constructed based on these genes, providing a theoretical basis for the treatment of TNBC patients. We confirm the model\u2019s validity in TNBC by validating SEPT3 (a key PyMRG) regulates TNBC cell proliferation, migration, and invasion.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s12672-026-05118-6","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T13:26:21Z","timestamp":1777555581000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating single-cell RNA and bulk RNA sequencing data to identify prognostic genes associated with pyrimidine metabolism in triple-negative breast cancer by machine learning algorithm combinations"],"prefix":"10.1007","volume":"17","author":[{"given":"Xue","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keru","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunbin","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"5118_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209\u201349.","journal-title":"CA Cancer J Clin"},{"key":"5118_CR2","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1001\/jama.2018.19323","volume":"321","author":"AG Waks","year":"2019","unstructured":"Waks AG, Winer EP. Breast Cancer Treatment: A Review. JAMA. 2019;321:288\u2013300.","journal-title":"JAMA"},{"key":"5118_CR3","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.clbc.2024.09.018","volume":"25","author":"S Gupta","year":"2025","unstructured":"Gupta S, Jones JE, Smith-Graziani D. Disparities in Hereditary Genetic Testing in Patients with Triple Negative Breast Cancer. Clin Breast Cancer. 2025;25:12\u2013e1811.","journal-title":"Clin Breast Cancer"},{"key":"5118_CR4","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1007\/s10549-023-07028-5","volume":"201","author":"W Chen","year":"2023","unstructured":"Chen W, Hu L, Lu X, Wang X, Zhao C, Guo C, Li X, Ding Y, Zhao H, Tong D, et al. The RNA binding protein MEX3A promotes tumor progression of breast cancer by post-transcriptional regulation of IGFBP4. Breast Cancer Res Treat. 2023;201:353\u201366.","journal-title":"Breast Cancer Res Treat"},{"key":"5118_CR5","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.jgg.2015.04.004","volume":"42","author":"MF Garavito","year":"2015","unstructured":"Garavito MF, Narv\u00e1ez-Ortiz HY, Zimmermann BH. Pyrimidine Metabolism: Dynamic and Versatile Pathways in Pathogens and Cellular Development. J Genet Genomics. 2015;42:195\u2013205.","journal-title":"J Genet Genomics"},{"key":"5118_CR6","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1186\/s13148-025-01956-3","volume":"17","author":"X Zhao","year":"2025","unstructured":"Zhao X, Mao S, Fang Y, Chen J, Bi L, Li J, Wu J, Gao J, Yang S, Fu J, et al. Landscape analysis of m5C modification regulators unveils DNMT1-mediated dysregulated pyrimidine metabolism in hepatocellular carcinoma. Clin Epigenetics. 2025;17:144.","journal-title":"Clin Epigenetics"},{"key":"5118_CR7","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1038\/s41556-023-01146-4","volume":"25","author":"C Yang","year":"2023","unstructured":"Yang C, Zhao Y, Wang L, Guo Z, Ma L, Yang R, Wu Y, Li X, Niu J, Chu Q, et al. De novo pyrimidine biosynthetic complexes support cancer cell proliferation and ferroptosis defence. Nat Cell Biol. 2023;25:836\u201347.","journal-title":"Nat Cell Biol"},{"key":"5118_CR8","doi-asserted-by":"publisher","first-page":"215837","DOI":"10.1016\/j.canlet.2022.215837","volume":"549","author":"D He","year":"2022","unstructured":"He D, Chen M, Chang L, Gu J, Liu F, Gao X, Ruan Y. De novo pyrimidine synthesis fuels glycolysis and confers chemoresistance in gastric cancer. Cancer Lett. 2022;549:215837.","journal-title":"Cancer Lett"},{"key":"5118_CR9","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1158\/2159-8290.CD-16-0611","volume":"7","author":"KK Brown","year":"2017","unstructured":"Brown KK, Spinelli JB, Asara JM, Toker A. Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer. Cancer Discov. 2017;7:391\u20139.","journal-title":"Cancer Discov"},{"key":"5118_CR10","doi-asserted-by":"publisher","first-page":"477","DOI":"10.3390\/biom11030477","volume":"11","author":"HY Zhi","year":"2021","unstructured":"Zhi HY, Zhao L, Lee CC, Chen CY. A novel graph neural network methodology to investigate dihydroorotate dehydrogenase inhibitors in small cell lung cancer. Biomolecules. 2021;11:477.","journal-title":"Biomolecules"},{"key":"5118_CR11","doi-asserted-by":"publisher","first-page":"119639","DOI":"10.1016\/j.bbamcr.2023.119639","volume":"1871","author":"RJ Mailloux","year":"2024","unstructured":"Mailloux RJ. Proline and dihydroorotate dehydrogenase promote a hyper-proliferative state and dampen ferroptosis in cancer cells by rewiring mitochondrial redox metabolism. Biochim Biophys Acta Mol Cell Res. 2024;1871:119639.","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"key":"5118_CR12","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1186\/s12885-024-12981-5","volume":"24","author":"FCA de Moraes","year":"2024","unstructured":"de Moraes FCA, de Almeida Barbosa AB, Sano VKT, Kelly FA, Burbano RMR. Pharmacogenetics of DPYD and treatment-related mortality on fluoropyrimidine chemotherapy for cancer patients: a meta-analysis and trial sequential analysis. BMC Cancer. 2024;24:1210.","journal-title":"BMC Cancer"},{"key":"5118_CR13","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1177\/1078155220904999","volume":"26","author":"A Botticelli","year":"2020","unstructured":"Botticelli A, Scagnoli S, Roberto M, Lionetto L, Cerbelli B, Simmaco M, Marchetti P. 5-Fluorouracil degradation rate as a predictive biomarker of toxicity in breast cancer patients treated with capecitabine. J Oncol Pharm Pract. 2020;26:1836\u201342.","journal-title":"J Oncol Pharm Pract"},{"key":"5118_CR14","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1021\/acsptsci.2c00117","volume":"5","author":"H Verma","year":"2022","unstructured":"Verma H, Narendra G, Raju B, Singh PK, Silakari O. Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution. ACS Pharmacol Transl Sci. 2022;5:1017\u201333.","journal-title":"ACS Pharmacol Transl Sci"},{"key":"5118_CR15","first-page":"787","volume":"2","author":"F Merloni","year":"2019","unstructured":"Merloni F, Ranallo N, Scortichini L, Giampieri R, Berardi R. Tailored therapy in patients treated with fluoropyrimidines: focus on the role of dihydropyrimidine dehydrogenase. Cancer Drug Resist. 2019;2:787\u2013802.","journal-title":"Cancer Drug Resist"},{"key":"5118_CR16","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1016\/j.clbc.2025.07.027","volume":"25","author":"JP Alzate-Granados","year":"2025","unstructured":"Alzate-Granados JP, Ni\u00f1o LF. Prediction of Overall and Relapse-Free Survival in Triple-Negative Breast Cancer Patients Through Machine Learning-Based Clustering on Clinical Data. Clin Breast Cancer. 2025;25:714\u20139.","journal-title":"Clin Breast Cancer"},{"key":"5118_CR17","doi-asserted-by":"publisher","first-page":"e707","DOI":"10.1016\/j.clbc.2025.04.008","volume":"25","author":"Y Song","year":"2025","unstructured":"Song Y, Wang C, Zhou Y, Sun Q, Lin Y. A Multi-Omics-Based Prognostic Model for Elderly Breast Cancer by Machine Learning: Insights From Hypoxia and Immunity of Tumor Microenvironment. Clin Breast Cancer. 2025;25:e707\u201319.","journal-title":"Clin Breast Cancer"},{"key":"5118_CR18","doi-asserted-by":"publisher","first-page":"e903","DOI":"10.1016\/j.clbc.2025.04.020","volume":"25","author":"Y Li","year":"2025","unstructured":"Li Y, Sundquist K, Wang X, Sundquist J, Memon AA. The Mitochondrial signature for predicting outcome of early-stage breast cancer by machine learning. Clin Breast Cancer. 2025;25:e903\u2013911.e4.","journal-title":"Clin Breast Cancer"},{"key":"5118_CR19","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1007\/s10549-025-07620-x","volume":"211","author":"G Liu","year":"2025","unstructured":"Liu G, Pan LZ, Chen J, Ma J. Unveiling the role of PANoptosis-related genes in breast cancer: an integrated study by multi-omics analysis and machine learning algorithms. Breast Cancer Res Treat. 2025;211:35\u201350.","journal-title":"Breast Cancer Res Treat"},{"key":"5118_CR20","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/s10549-024-07574-6","volume":"210","author":"M Yue","year":"2025","unstructured":"Yue M, Zhao J, Wu S, Cai L, Wang X, Jia Y, Wang X, Wang Y, Liu Y. Establishment of multiple machine learning prognostic model for gene differences between primary tumors and lymph nodes in luminal breast cancer. Breast Cancer Res Treat. 2025;210:365\u201376.","journal-title":"Breast Cancer Res Treat"},{"key":"5118_CR21","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1134\/S0006297923020074","volume":"88","author":"AA Khozyainova","year":"2023","unstructured":"Khozyainova AA, Valyaeva AA, Arbatsky MS, Isaev SV, Iamshchikov PS, Volchkov EV, Sabirov MS, Zainullina VR, Chechekhin VI, Vorobev RS, et al. Complex Analysis of Single-Cell RNA Sequencing Data. Biochem (Mosc). 2023;88:231\u201352.","journal-title":"Biochem (Mosc)"},{"key":"5118_CR22","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1038\/s41573-023-00688-4","volume":"22","author":"B Van de Sande","year":"2023","unstructured":"Van de Sande B, Lee JS, Mutasa-Gottgens E, Naughton B, Bacon W, Manning J, Wang Y, Pollard J, Mendez M, Hill J, et al. Applications of single-cell RNA sequencing in drug discovery and development. Nat Rev Drug Discov. 2023;22:496\u2013520.","journal-title":"Nat Rev Drug Discov"},{"key":"5118_CR23","doi-asserted-by":"publisher","first-page":"1164930","DOI":"10.3389\/fendo.2023.1164930","volume":"14","author":"P He","year":"2023","unstructured":"He P, Ma Y, Wu Y, Zhou Q, Du H. Exploring PANoptosis in breast cancer based on scRNA-seq and bulk-seq. Front Endocrinol (Lausanne). 2023;14:1164930.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"5118_CR24","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1186\/s12931-024-02954-4","volume":"25","author":"D Zhang","year":"2024","unstructured":"Zhang D, Pu X, Zheng M, Li G, Chen J. Employing a synergistic bioinformatics and machine learning framework to elucidate biomarkers associating asthma with pyrimidine metabolism genes. Respir Res. 2024;25:327.","journal-title":"Respir Res"},{"key":"5118_CR25","doi-asserted-by":"publisher","first-page":"1200054","DOI":"10.3389\/fphar.2023.1200054","volume":"14","author":"C Li","year":"2023","unstructured":"Li C, Zhang K, Gong Y, Wu Q, Zhang Y, Dong Y, Li D, Wang Z. Based on cuproptosis-related lncRNAs, a novel prognostic signature for colon adenocarcinoma prognosis, immunotherapy, and chemotherapy response. Front Pharmacol. 2023;14:1200054.","journal-title":"Front Pharmacol"},{"key":"5118_CR26","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","volume":"9","author":"P Langfelder","year":"2008","unstructured":"Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559.","journal-title":"BMC Bioinformatics"},{"key":"5118_CR27","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.","journal-title":"Genome Biol"},{"key":"5118_CR28","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1007\/s10495-023-01868-8","volume":"28","author":"Y Shi","year":"2023","unstructured":"Shi Y, Wang Y, Dong H, Niu K, Zhang W, Feng K, Yang R, Zhang Y. Crosstalk of ferroptosis regulators and tumor immunity in pancreatic adenocarcinoma: novel perspective to mRNA vaccines and personalized immunotherapy. Apoptosis. 2023;28:1423\u201335.","journal-title":"Apoptosis"},{"key":"5118_CR29","doi-asserted-by":"publisher","first-page":"e43","DOI":"10.1002\/imt2.43","volume":"1","author":"Z Gu","year":"2022","unstructured":"Gu Z. Complex heatmap visualization. Imeta. 2022;1:e43.","journal-title":"Imeta"},{"key":"5118_CR30","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/1471-2105-12-35","volume":"12","author":"H Chen","year":"2011","unstructured":"Chen H, Boutros PC. VennDiagram: a package for the generation of highly-customizable Venn and Euler diagrams in R. BMC Bioinformatics. 2011;12:35.","journal-title":"BMC Bioinformatics"},{"key":"5118_CR31","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","volume":"16","author":"G Yu","year":"2012","unstructured":"Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics. 2012;16:284\u20137.","journal-title":"Omics"},{"key":"5118_CR32","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1002\/bimj.202000382","volume":"64","author":"KM Beyene","year":"2022","unstructured":"Beyene KM, El Ghouch A. Time-dependent ROC curve estimation for interval-censored data. Biom J. 2022;64:1056\u201374.","journal-title":"Biom J"},{"key":"5118_CR33","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s12967-023-04029-2","volume":"21","author":"P Zhao","year":"2023","unstructured":"Zhao P, Zhen H, Zhao H, Huang Y, Cao B. Identification of hub genes and potential molecular mechanisms related to radiotherapy sensitivity in rectal cancer based on multiple datasets. J Transl Med. 2023;21:176.","journal-title":"J Transl Med"},{"key":"5118_CR34","doi-asserted-by":"publisher","first-page":"6241","DOI":"10.2147\/JIR.S442388","volume":"16","author":"H Shi","year":"2023","unstructured":"Shi H, Yuan X, Liu G, Fan W. Identifying and Validating GSTM5 as an Immunogenic Gene in Diabetic Foot Ulcer Using Bioinformatics and Machine Learning. J Inflamm Res. 2023;16:6241\u201356.","journal-title":"J Inflamm Res"},{"key":"5118_CR35","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1186\/s12859-015-0716-8","volume":"16","author":"V Weyer","year":"2015","unstructured":"Weyer V, Binder H. A weighting approach for judging the effect of patient strata on high-dimensional risk prediction signatures. BMC Bioinformatics. 2015;16:294.","journal-title":"BMC Bioinformatics"},{"key":"5118_CR36","doi-asserted-by":"publisher","first-page":"3206","DOI":"10.1093\/bioinformatics\/btr511","volume":"27","author":"MS Schr\u00f6der","year":"2011","unstructured":"Schr\u00f6der MS, Culhane AC, Quackenbush J, Haibe-Kains B. survcomp: an R\/Bioconductor package for performance assessment and comparison of survival models. Bioinformatics. 2011;27:3206\u20138.","journal-title":"Bioinformatics"},{"key":"5118_CR37","doi-asserted-by":"publisher","first-page":"e0291645","DOI":"10.1371\/journal.pone.0291645","volume":"18","author":"Q Feng","year":"2023","unstructured":"Feng Q, Lu H, Wu L. Identification of M2-like macrophage-related signature for predicting the prognosis, ecosystem and immunotherapy response in hepatocellular carcinoma. PLoS ONE. 2023;18:e0291645.","journal-title":"PLoS ONE"},{"key":"5118_CR38","doi-asserted-by":"publisher","first-page":"3388","DOI":"10.1002\/sim.5753","volume":"32","author":"DF McCaffrey","year":"2013","unstructured":"McCaffrey DF, Griffin BA, Almirall D, Slaughter ME, Ramchand R, Burgette LF. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Stat Med. 2013;32:3388\u2013414.","journal-title":"Stat Med"},{"key":"5118_CR39","doi-asserted-by":"publisher","first-page":"101784","DOI":"10.1016\/j.tranon.2023.101784","volume":"38","author":"D Ding","year":"2023","unstructured":"Ding D, Wang L, Zhang Y, Shi K, Shen Y. Machine learning developed a programmed cell death signature for predicting prognosis and immunotherapy benefits in lung adenocarcinoma. Transl Oncol. 2023;38:101784.","journal-title":"Transl Oncol"},{"key":"5118_CR40","doi-asserted-by":"publisher","first-page":"15360","DOI":"10.18632\/aging.205354","volume":"15","author":"M Ding","year":"2023","unstructured":"Ding M, Ran X, Qian S, Zhang Y, Wang Z, Dong M, Yang Z, Wu S, Feng X, Zhang J, et al. Clinical and therapeutical significances of the cluster and signature based on oxidative stress for osteosarcoma. Aging. 2023;15:15360\u201381.","journal-title":"Aging"},{"key":"5118_CR41","doi-asserted-by":"publisher","first-page":"e21147","DOI":"10.1016\/j.heliyon.2023.e21147","volume":"9","author":"J Xu","year":"2023","unstructured":"Xu J, Yang T, Wu F, Chen T, Wang A, Hou S. A nomogram for predicting prognosis of patients with cervical cerclage. Heliyon. 2023;9:e21147.","journal-title":"Heliyon"},{"key":"5118_CR42","doi-asserted-by":"publisher","first-page":"883404","DOI":"10.3389\/fimmu.2022.883404","volume":"13","author":"Y Wang","year":"2022","unstructured":"Wang Y, Li B, Zhao Y. Inflammation in Preeclampsia: Genetic Biomarkers, Mechanisms, and Therapeutic Strategies. Front Immunol. 2022;13:883404.","journal-title":"Front Immunol"},{"key":"5118_CR43","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1101\/gr.239244.118","volume":"28","author":"A Mayakonda","year":"2018","unstructured":"Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28:1747\u201356.","journal-title":"Genome Res"},{"key":"5118_CR44","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","volume":"184","author":"Y Hao","year":"2021","unstructured":"Hao Y, Hao S, Andersen-Nissen E, Mauck WM, Zheng S, Butler A, Lee MJ, Wilk AJ, Darby C, Zager M, et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184:3573\u2013e35873529.","journal-title":"Cell"},{"key":"5118_CR45","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1038\/s41597-023-02709-8","volume":"10","author":"S Gul","year":"2023","unstructured":"Gul S, Pang J, Yuan H, Chen Y, Yu Q, Wang H, Tang W. Stemness signature and targeted therapeutic drugs identification for Triple Negative Breast Cancer. Sci Data. 2023;10:815.","journal-title":"Sci Data"},{"key":"5118_CR46","doi-asserted-by":"publisher","first-page":"2115","DOI":"10.1074\/mcp.TIR120.002155","volume":"19","author":"J Griss","year":"2020","unstructured":"Griss J, Viteri G, Sidiropoulos K, Nguyen V, Fabregat A, Hermjakob H. ReactomeGSA - Efficient Multi-Omics Comparative Pathway Analysis. Mol Cell Proteom. 2020;19:2115\u201325.","journal-title":"Mol Cell Proteom"},{"key":"5118_CR47","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","volume":"12","author":"S Jin","year":"2021","unstructured":"Jin S, Guerrero-Juarez CF, Zhang L, Chang I, Ramos R, Kuan CH, Myung P, Plikus MV, Nie Q. Inference and analysis of cell-cell communication using CellChat. Nat Commun. 2021;12:1088.","journal-title":"Nat Commun"},{"key":"5118_CR48","doi-asserted-by":"publisher","first-page":"e107468","DOI":"10.1371\/journal.pone.0107468","volume":"9","author":"P Geeleher","year":"2014","unstructured":"Geeleher P, Cox N, Huang RS. pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS ONE. 2014;9:e107468.","journal-title":"PLoS ONE"},{"key":"5118_CR49","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s13058-016-0799-9","volume":"19","author":"H Ma","year":"2017","unstructured":"Ma H, Ursin G, Xu X, Lee E, Togawa K, Duan L, Lu Y, Malone KE, Marchbanks PA, McDonald JA, et al. Reproductive factors and the risk of triple-negative breast cancer in white women and African-American women: a pooled analysis. Breast Cancer Res. 2017;19:6.","journal-title":"Breast Cancer Res"},{"key":"5118_CR50","doi-asserted-by":"publisher","DOI":"10.1016\/j.clbc.2025.07.005","author":"YA de Civil","year":"2025","unstructured":"Civil YA, Purcell ND, de Vries R, Oei AL, Thijssen V, de Gruijl TD, Slotman BJ, Schneiders FL, van den Bongard H. Prognostic value of tumor-infiltrating lymphocytes in breast cancer patients treated with radiotherapy: a systematic review of literature. Clin Breast Cancer. 2025. https:\/\/doi.org\/10.1016\/j.clbc.2025.07.005.","journal-title":"Clin Breast Cancer"},{"key":"5118_CR51","doi-asserted-by":"publisher","first-page":"117268","DOI":"10.1016\/j.ejmech.2025.117268","volume":"286","author":"Y An","year":"2025","unstructured":"An Y, Lv X, Xu S, Li H, Zheng P, Zhu W, Wang L. Pyrimidine-based dual-target inhibitors targeting epidermal growth factor receptor for overcoming drug resistance in cancer therapy(2006-present). Eur J Med Chem. 2025;286:117268.","journal-title":"Eur J Med Chem"},{"key":"5118_CR52","doi-asserted-by":"publisher","first-page":"216993","DOI":"10.1016\/j.canlet.2024.216993","volume":"596","author":"Z Chow","year":"2024","unstructured":"Chow Z, Johnson J, Chauhan A, Jeong JC, Castle JT, Izumi T, Weiss H, Townsend CM Jr., Schrader J, Anthony L, et al. Inhibition of ribonucleotide reductase subunit M2 enhances the radiosensitivity of metastatic pancreatic neuroendocrine tumor. Cancer Lett. 2024;596:216993.","journal-title":"Cancer Lett"},{"key":"5118_CR53","doi-asserted-by":"publisher","first-page":"217514","DOI":"10.1016\/j.canlet.2025.217514","volume":"613","author":"Y Xue","year":"2025","unstructured":"Xue Y, Chen T, Ma Z, Pu X, Xu J, Zhai S, Du X, Ji Y, Simon MC, Zhai W, Xue W. Osalmid sensitizes clear cell renal cell carcinoma to navitoclax through a STAT3\/BCL-XL pathway. Cancer Lett. 2025;613:217514.","journal-title":"Cancer Lett"},{"key":"5118_CR54","doi-asserted-by":"publisher","first-page":"116332","DOI":"10.1016\/j.biopha.2024.116332","volume":"173","author":"A Taiyab","year":"2024","unstructured":"Taiyab A, Choudhury A, Haidar S, Yousuf M, Rathi A, Koul P, Chakrabarty A, Islam A, Shamsi A, Hassan MI. Exploring MTH1 inhibitory potential of Thymoquinone and Baicalin for therapeutic targeting of breast cancer. Biomed Pharmacother. 2024;173:116332.","journal-title":"Biomed Pharmacother"},{"key":"5118_CR55","doi-asserted-by":"publisher","first-page":"5626","DOI":"10.1038\/s41598-025-90159-0","volume":"15","author":"H Xiao","year":"2025","unstructured":"Xiao H, Ni J, Yu Q. Identification of ECE2 signaling in promoting non-small lung cancer progression through ET1\/YAP1\/MAGEA3 axis. Sci Rep. 2025;15:5626.","journal-title":"Sci Rep"},{"issue":"4","key":"5118_CR56","first-page":"39","volume":"36","author":"W Gu Xinye","year":"2021","unstructured":"Gu Xinye W, Danping JB, Shang Jiangfeng J, Guoqin W, Jinrong L, Hua. ECE2 Promotes Proliferation and Migration of Breast Cancer Cells by Upregulation of E2F1 and MYC. J Mod Lab Med. 2021;36(4):39\u201344.","journal-title":"J Mod Lab Med"},{"key":"5118_CR57","doi-asserted-by":"publisher","first-page":"zcad032","DOI":"10.1093\/narcan\/zcad032","volume":"5","author":"MR Pandkar","year":"2023","unstructured":"Pandkar MR, Raveendran A, Biswas K, Mutnuru SA, Mishra J, Samaiya A, Malys T, Mitrophanov AY, Sharan SK, Shukla S. PKM2 dictates the poised chromatin state of PFKFB3 promoter to enhance breast cancer progression. NAR Cancer. 2023;5:zcad032.","journal-title":"NAR Cancer"},{"key":"5118_CR58","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s12935-023-03201-4","volume":"24","author":"X Wang","year":"2024","unstructured":"Wang X, Zhang J, Wu Y, Zhang Y, Zhang S, Li A, Wang J, Wang Z. ROR\u03b1 inhibits gastric cancer proliferation through attenuating G6PD and PFKFB3 induced glycolytic activity. Cancer Cell Int. 2024;24:12.","journal-title":"Cancer Cell Int"},{"key":"5118_CR59","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1002\/mc.23177","volume":"59","author":"Z Shao","year":"2020","unstructured":"Shao Z, Ma X, Zhang Y, Sun Y, Lv W, He K, Xia R, Wang P, Gao X. CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple-negative breast cancer. Mol Carcinog. 2020;59:533\u201344.","journal-title":"Mol Carcinog"},{"key":"5118_CR60","doi-asserted-by":"publisher","first-page":"101242","DOI":"10.1016\/j.plipres.2023.101242","volume":"92","author":"KSD Kothapalli","year":"2023","unstructured":"Kothapalli KSD, Park HG, Kothapalli NSL, Brenna JT. FADS2 function at the major cancer hotspot 11q13 locus alters fatty acid metabolism in cancer. Prog Lipid Res. 2023;92:101242.","journal-title":"Prog Lipid Res"},{"key":"5118_CR61","doi-asserted-by":"publisher","first-page":"1074242","DOI":"10.3389\/fimmu.2023.1074242","volume":"14","author":"T Zhao","year":"2023","unstructured":"Zhao T, Gao P, Li Y, Tian H, Ma D, Sun N, Chen C, Zhang Y, Qi X. Investigating the role of FADS family members in breast cancer based on bioinformatic analysis and experimental validation. Front Immunol. 2023;14:1074242.","journal-title":"Front Immunol"},{"key":"5118_CR62","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.1038\/s44321-024-00090-6","volume":"16","author":"N Lorito","year":"2024","unstructured":"Lorito N, Subbiani A, Smiriglia A, Bacci M, Bonechi F, Tronci L, Romano E, Corrado A, Longo DL, Iozzo M, et al. FADS1\/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer. EMBO Mol Med. 2024;16:1533\u201359.","journal-title":"EMBO Mol Med"},{"key":"5118_CR63","doi-asserted-by":"publisher","first-page":"1390882","DOI":"10.3389\/fgene.2024.1390882","volume":"15","author":"H Li","year":"2024","unstructured":"Li H, Qian F, Bao S. Identification and functional analysis of lactic acid metabolism-related differentially expressed genes in hepatocellular carcinoma. Front Genet. 2024;15:1390882.","journal-title":"Front Genet"},{"key":"5118_CR64","doi-asserted-by":"publisher","first-page":"4731349","DOI":"10.1155\/2021\/4731349","volume":"2021","author":"K Huang","year":"2021","unstructured":"Huang K, Wu Y, Xie Y, Huang L, Liu H. Analyzing mRNAsi-Related Genes Identifies Novel Prognostic Markers and Potential Drug Combination for Patients with Basal Breast Cancer. Dis Markers. 2021;2021:4731349.","journal-title":"Dis Markers"},{"key":"5118_CR65","doi-asserted-by":"publisher","first-page":"107102","DOI":"10.1016\/j.cmpb.2022.107102","volume":"226","author":"T Chen","year":"2022","unstructured":"Chen T, Xu B, Chen H, Sun Y, Song J, Sun X, Zhang X, Hua W. Transcription factor NFE2L3 promotes the proliferation of esophageal squamous cell carcinoma cells and causes radiotherapy resistance by regulating IL-6. Comput Methods Programs Biomed. 2022;226:107102.","journal-title":"Comput Methods Programs Biomed"},{"key":"5118_CR66","first-page":"123","volume":"40","author":"C Zheng","year":"2025","unstructured":"Zheng C, Pan Y, Lin B, Li J, Chen Q, Zheng Z. NRF3 suppresses the metastasis of triple-negative breast cancer cells by inhibiting ERK activation in a ROS-dependent manner. Histol Histopathol. 2025;40:123\u201331.","journal-title":"Histol Histopathol"},{"key":"5118_CR67","doi-asserted-by":"publisher","first-page":"2416221","DOI":"10.1080\/15384047.2024.2416221","volume":"25","author":"P Xing","year":"2024","unstructured":"Xing P, Chen Z, Zhu W, Lin B, Quan M. NRF3 suppresses the malignant progression of TNBC by promoting M1 polarization of macrophages via ROS\/HMGB1 axis. Cancer Biol Ther. 2024;25:2416221.","journal-title":"Cancer Biol Ther"},{"key":"5118_CR68","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1093\/carcin\/bgx022","volume":"38","author":"J Ding","year":"2017","unstructured":"Ding J, Kuo ML, Su L, Xue L, Luh F, Zhang H, Wang J, Lin TG, Zhang K, Chu P, et al. Human mitochondrial pyrroline-5-carboxylate reductase 1 promotes invasiveness and impacts survival in breast cancers. Carcinogenesis. 2017;38:519\u201331.","journal-title":"Carcinogenesis"},{"key":"5118_CR69","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/s41419-023-06200-5","volume":"14","author":"B Cui","year":"2023","unstructured":"Cui B, He B, Huang Y, Wang C, Luo H, Lu J, Su K, Zhang X, Luo Y, Zhao Z, et al. Pyrroline-5-carboxylate reductase 1 reprograms proline metabolism to drive breast cancer stemness under psychological stress. Cell Death Dis. 2023;14:682.","journal-title":"Cell Death Dis"},{"key":"5118_CR70","first-page":"529","volume":"13","author":"BWK Wardhani","year":"2021","unstructured":"Wardhani BWK, Louisa M, Watanabe Y, Setiabudy R, Kato M. TGF-\u03b2-Induced TMEPAI Promotes Epithelial-Mesenchymal Transition in Doxorubicin-Treated Triple-Negative Breast Cancer Cells via SMAD3 and PI3K\/AKT Pathway Alteration. Breast Cancer (Dove Med Press). 2021;13:529\u201338.","journal-title":"Breast Cancer (Dove Med Press)"},{"key":"5118_CR71","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.3390\/life11121396","volume":"11","author":"HL Lu","year":"2021","unstructured":"Lu HL, Wu KC, Chen CW, Weng HK, Huang BM, Lin TY, Liu MH, So EC, Lin RM, Wang YK. Anticancer effects of midazolam on lung and breast cancers by inhibiting cell proliferation and epithelial-mesenchymal transition. Life. 2021;11:1396.","journal-title":"Life"},{"key":"5118_CR72","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1186\/s12943-024-02138-0","volume":"23","author":"KJ Ryu","year":"2024","unstructured":"Ryu KJ, Lee KW, Park SH, Kim T, Hong KS, Kim H, Kim M, Ok DW, Kwon GNB, Park YJ, et al. Chaperone-mediated autophagy modulates Snail protein stability: implications for breast cancer metastasis. Mol Cancer. 2024;23:227.","journal-title":"Mol Cancer"},{"key":"5118_CR73","doi-asserted-by":"publisher","first-page":"7430","DOI":"10.3390\/ijms26157430","volume":"26","author":"TM Mohiuddin","year":"2025","unstructured":"Mohiuddin TM, Sheng W, Zhang C, Al-Rawe M, Tchaikovski S, Zeppernick F, Meinhold-Heerlein I, Hussain AF. Multiplex immunofluorescence reveals therapeutic targets EGFR, EpCAM, tissue factor, and TROP2 in triple-negative breast cancer. Int J Mol Sci. 2025;26:7430.","journal-title":"Int J Mol Sci"},{"key":"5118_CR74","doi-asserted-by":"publisher","first-page":"546","DOI":"10.3390\/cimb47070546","volume":"47","author":"F Yuan","year":"2025","unstructured":"Yuan F, Qiao Y, Chen Z, He H, Wang F, Chen J. Molecular mechanisms of Lobelia nummularia extract in breast cancer: targeting EGFR\/TP53 and PI3K-AKT-mTOR signaling via ROS-Mediated apoptosis. Curr Issues Mol Biol. 2025;47:546.","journal-title":"Curr Issues Mol Biol"},{"key":"5118_CR75","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.2147\/IJGM.S462541","volume":"17","author":"LH Yang","year":"2024","unstructured":"Yang LH, Wang GZ, Gao C. SEPT3 as a Potential Molecular Target of Triple-Negative Breast Cancer. Int J Gen Med. 2024;17:1605\u201313.","journal-title":"Int J Gen Med"},{"key":"5118_CR76","doi-asserted-by":"publisher","first-page":"247","DOI":"10.3390\/pharmaceutics17020247","volume":"17","author":"M S\u00e1nchez-D\u00edez","year":"2025","unstructured":"S\u00e1nchez-D\u00edez M, Romero-Jim\u00e9nez P, Alegr\u00eda-Aravena N, Gavira-O\u2019Neill CE, Vicente-Garc\u00eda E, Quiroz-Troncoso J, Gonz\u00e1lez-Martos R, Ram\u00edrez-Castillejo C, Pastor JM. Assessment of cell viability in drug therapy: IC50 and other new time-independent indices for evaluating chemotherapy efficacy. Pharmaceutics. 2025;17:247.","journal-title":"Pharmaceutics"},{"key":"5118_CR77","doi-asserted-by":"publisher","first-page":"901392","DOI":"10.3389\/fmolb.2022.901392","volume":"9","author":"G Green-Tripp","year":"2022","unstructured":"Green-Tripp G, Nattress C, Halld\u00e9n G. Targeting Triple Negative Breast Cancer With Oncolytic Adenoviruses. Front Mol Biosci. 2022;9:901392.","journal-title":"Front Mol Biosci"},{"key":"5118_CR78","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.1002\/ajh.27470","volume":"99","author":"SM Ansell","year":"2024","unstructured":"Ansell SM. Hodgkin lymphoma: 2025 update on diagnosis, risk-stratification, and management. Am J Hematol. 2024;99:2367\u201378.","journal-title":"Am J Hematol"},{"key":"5118_CR79","doi-asserted-by":"publisher","first-page":"2640","DOI":"10.1158\/1535-7163.MCT-13-0066","volume":"12","author":"H Shao","year":"2013","unstructured":"Shao H, Jing K, Mahmoud E, Huang H, Fang X, Yu C. Apigenin sensitizes colon cancer cells to antitumor activity of ABT-263. Mol Cancer Ther. 2013;12:2640\u201350.","journal-title":"Mol Cancer Ther"}],"container-title":["Discover Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12672-026-05118-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-026-05118-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-026-05118-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T02:04:35Z","timestamp":1781748275000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12672-026-05118-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,30]]},"references-count":79,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["5118"],"URL":"https:\/\/doi.org\/10.1007\/s12672-026-05118-6","relation":{},"ISSN":["2730-6011"],"issn-type":[{"value":"2730-6011","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,30]]},"assertion":[{"value":"6 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All programs followed were according to the ethical standards of the Human Subjects Responsibility Committee (institutions and countries) and the 1964 Helsinki Declaration and subsequent editions. This research was approved by the Ethics Committee of the Harbin Medical University Cancer Hospital (Registration number KY2024-15). A copy of the written consent form is available for review by the editor-in-chief of this journal upon request. All participants have signed written informed consent forms. A copy of the written consent form is available for review by the editor-in-chief of this journal upon request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"916"}}