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We investigated TFAP2B, an AP-2 family transcription factor linked to epithelial differentiation, and FOXC1, a basal-like-associated transcription factor, as complementary markers of luminal and basal differentiation in TNBC. In a tissue microarray of 105 TNBCs, tumors were stratified as TFAP2B-dominant, FOXC1-dominant, or double-negative according to relative marker predominance and characterized using lineage, proliferation, molecular, immune, and chemotherapy-response parameters. TFAP2B-dominant tumors were associated with a coherent luminal phenotype, including apocrine\/lobular enrichment, strong MUCL1 and AR expression, high CK18, low SOX10, reduced proliferation, frequent wild-type p53 patterns and retained RB1 expression, and low PD-L1 expression. FOXC1-dominant tumors showed contrasting basal-like features. These associations were independently supported at the transcriptional and genomic levels in the METABRIC TNBC cohort. FOXC1-dominant tumors also showed more frequent chemotherapy-induced downstaging than TFAP2B-dominant tumors. Together, we identify TFAP2B as a marker associated with luminal differentiation in TNBC and support combined TFAP2B\/FOXC1 assessment as a practical framework for identifying clinically relevant TNBC differentiation states.<\/jats:p>","DOI":"10.1038\/s41598-026-68832-9","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T06:44:59Z","timestamp":1789109099000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TFAP2B and FOXC1 are associated with biologically and clinically distinct differentiation states in triple-negative breast cancer"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2530-5519","authenticated-orcid":false,"given":"Franz-Leonard","family":"Klaus","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Kitzke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Kiechle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Mogler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Muckenhuber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"68832_CR1","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1038\/nrclinonc.2016.66","volume":"13","author":"G Bianchini","year":"2016","unstructured":"Bianchini, G., Balko, J. 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The study was conducted in accordance with the Declaration of Helsinki. Archival biomaterial was used in accordance with the ethics approval and applicable institutional and legal requirements. Due to the retrospective nature of the study, the Ethics Committee of the Technical University of Munich waived the need for obtaining informed consent.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"CM is a member of the MSD advisory board. EK reports payment or honoraria for lectures, presentations, speaker\u2019s bureaus, manuscript writing or educational events from Novartis Pharma Gmbh, FomF GmbH, AstraZeneca GmbH,\u00a0Eurobio scientific (former: Myriad genetics GmbH). MK is PI of the RESCUE Study and has the following COIs: Renumeration: Springer Press, Biermann Press, Celgene, Astra Zeneca, Myriad Genetics, TEVA, Eli Lilly, GSK, Seagen, AllergoSan, NutriImmun, FOMF, Roche, BESINS, Jenapharm, Bayer AG, Pierre Fabre, Abbvie. Consultant\/advisory role:\u00a0Myriad Genetics, Bavarian KVB, Roche, DKMS Life, BLAEK, TEVA, Exeltis, BESINS, Bayer AG, Eurobio-Scientific, Magna Med Group. Equity owner:\u00a0AIM GmbH, In Manas GmbH, Therawis Diagnostic GmbH. Funding: Sphingotec, Deutsche Krebshilfe, DFG, Senator Roesner Foundation, Dr. Pommer-Jung Foundation, Waltraut Bergmann Foundation, Bavarian State Ministry of Economy, BMBF, Innovation Fond GBA, Bavarian Ministry of Health and Prevention. AM has a consultancy contract with Biontech SE, Mainz.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"28458"}}