{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:51:14Z","timestamp":1791204674481,"version":"4.2.0"},"reference-count":95,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","award":["No. 2024AFD433"],"award-info":[{"award-number":["No. 2024AFD433"]}],"id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    Estrogen receptor-negative\/progesterone receptor-positive\/human epidermal growth factor receptor 2-negative (ER\n                    <jats:sup>-<\/jats:sup>\n                    \/PR\n                    <jats:sup>+<\/jats:sup>\n                    \/HER2\n                    <jats:sup>-<\/jats:sup>\n                    )breast cancer is a rare, controversial type that makes up about 0. 3% of all breast cancer cases and does not follow the traditional ER\u2192PR regulatory hierarchy. This review synthesizes the available evidence on the diagnostic evaluation, clinicopathological characteristics, molecular mechanisms, prognosis, and treatment of ER\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/PR\n                    <jats:sup>+<\/jats:sup>\n                    \/HER2\n                    <jats:sup>\u2212<\/jats:sup>\n                    (ER\n                    <jats:sup>-<\/jats:sup>\n                    \/PR\n                    <jats:sup>+<\/jats:sup>\n                    ) breast cancer. Although there are false-negative ER staining results and pre-analytical\/analytical factors, a number of clinical and transcriptomic data support the existence of a reproducible ER\n                    <jats:sup>-<\/jats:sup>\n                    \/PR\n                    <jats:sup>+<\/jats:sup>\n                    subgroup with molecular heterogeneity. These tumors often have a high histological grade, elevated Ki-67 expression, TP53 alterations, and basal-like features, and are closer to triple-negative breast cancer than luminal disease. Potential drivers include ER-independent non-canonical PR activation, epigenetic dysregulation, kinase-mediated receptor phosphorylation, membrane-associated progesterone signaling and receptor network reprogramming. Direct subtype-specific evidence remains limited, and the effectiveness of conventional endocrine therapy is unknown. Current guidelines classify these tumors as hormone receptor-positive\/HER2-negative, obscuring clinically relevant heterogeneity. Standardized repeat testing and multi-omic characterization are thus required. Future studies should prioritize prospective multicenter cohorts with paired pre-treatment and post-treatment receptor testing, spatial or single-cell characterization, biomarker-guided stratification and adaptive clinical trials. A PR-oriented precision-medicine framework may improve diagnostic classification and help identify therapeutic vulnerabilities in biologically distinct patient subsets. In addition, this rare phenotype may serve as a useful model for investigating lineage plasticity and endocrine resistance.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1961666","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:56:56Z","timestamp":1791201416000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ER-\/PR+ breast cancer: from diagnostic discordance to precision therapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Yuanhao","family":"Shao","sequence":"first","affiliation":[{"name":"Department of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenwei","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology","place":["Wuhan, China"]},{"name":"Department of Orthopedics, Union Hospital,Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Thyroid and Breast Surgery, Union Hospital, 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