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Here, we profiled eRNA expression across 1073 The Cancer Genome Atlas Breast Cancer (TCGA-BRCA) samples integrated with The Cancer eRNA Atlas annotations, using GTEx healthy breast tissue (n = 179) as a curated normal reference. For prognostic stratification, least absolute shrinkage and selection operator (LASSO)-Cox regression identified a 10-eRNA signature that stratified patients into high- and low-risk groups in both training (P &amp;lt;.0001) and independent testing cohorts (P = 0.0022), with a 3-year time-dependent area under the curve (AUC) of 0.743. Multivariate Cox analysis confirmed the signature as an independent predictor [hazard ratio = 3.176, 95% confidence interval (CI): 2.075\u20134.864,\u00a0P &amp;lt;.001]. Multi-omics network integration linked these prognostic eRNAs to regulatory hubs centered on the\u00a0ESR1\/FOXA1\/GATA3\/AR axis. For early-stage detection, we developed a 19-eRNA panel via bootstrap LASSO feature selection and benchmarked ten classifiers; a Multilayer Perceptron achieved the best generalization (AUC = 0.959, 95% CI: 0.925\u20130.986) on an independent cohort (GSE225846). Both modules were deployed in eRNACare, a publicly accessible web application for individualized survival and tumor probability scoring. These findings establish eRNAs as a complementary noncoding layer to conventional messenger RNA classifiers, with clinical potential for breast cancer risk stratification, therapeutic guidance, and early detection.<\/jats:p>","DOI":"10.1093\/narcan\/zcag026","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:34:55Z","timestamp":1788867295000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrative multi-omics profiling and machine learning reveal enhancer RNA signatures for early detection and prognostic stratification in breast cancer"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8876-0154","authenticated-orcid":false,"given":"Junhuan","family":"Xia","sequence":"first","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University , No. 2 SEU Road, Nanjing 211189, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Tian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University , No. 2 SEU Road, Nanjing 211189, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3607-7456","authenticated-orcid":false,"given":"Yuting","family":"Cao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University , No. 2 SEU Road, Nanjing 211189, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhan","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University , No. 2 SEU Road, Nanjing 211189, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiye","family":"Qian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University , No. 2 SEU Road, Nanjing 211189, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Qi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University , No. 2 SEU Road, Nanjing 211189, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5570-6145","authenticated-orcid":false,"given":"Hao","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, 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