{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:02:01Z","timestamp":1770814921624,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aggressive breast cancer subtypes, such as triple-negative breast cancer (TNBC) and tumors in BRCA1 germline mutation carriers, present significant clinical challenges. The role of BRCA1 protein expression, assessed via immunohistochemistry (IHC), in defining the biology of these high-risk tumors remains to be fully elucidated. We performed a semi-quantitative IHC analysis of BRCA1 protein expression in a targeted cohort of 100 invasive breast carcinomas, enriched for TNBC (88%) and BRCA1 mutation carriers (34%). A validated monoclonal antibody and a composite scoring system (0\u20139) were employed, with an optimal cut-off defined by ROC analysis. Associations with clinicopathological parameters and p16 expression were evaluated. Low BRCA1 expression was strongly associated with an aggressive phenotype, including invasive ductal histology, hormone receptor negativity, and the TNBC subtype (all p &lt; 0.001). Tumors with BRCA1 loss exhibited a more pro-tumorigenic microenvironment, characterized by higher rates of necrosis (p = 0.014) and denser mononuclear infiltrates (p = 0.019). A significant inverse correlation with p16 overexpression was identified (p = 0.030). Our findings demonstrate that BRCA1 protein loss delineates a distinct aggressive tumor biology within high-risk breast cancers. We emphasize that BRCA1 IHC is a complementary biomarker and cannot supplant germline genetic testing for clinical decision-making regarding targeted therapies.<\/jats:p>","DOI":"10.3390\/ijms27041729","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T09:15:12Z","timestamp":1770801312000},"page":"1729","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Semi-Quantitative Evaluation of BRCA1 Protein in Breast Tumors Using Anti-BRCA1 Antibodies: Clinical Implications"],"prefix":"10.3390","volume":"27","author":[{"given":"Sorana Caterina","family":"Anton","sequence":"first","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0024-0237","authenticated-orcid":false,"given":"Alin Horatiu","family":"Nedelcu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2191-6697","authenticated-orcid":false,"given":"Victor","family":"Ianole","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Department of Pathology, \u201cProf. Dr. Nicolae Oblu\u201d Emergency Clinical Hospital, 700309 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7717-1738","authenticated-orcid":false,"given":"Carmen","family":"Anton","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Department of Pathology, \u201cSaint Spiridon\u201d County Hospital, 700111 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0194-7832","authenticated-orcid":false,"given":"Mihai","family":"Danciu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Department of Pathology, \u201cSaint Spiridon\u201d County Hospital, 700111 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7083-8197","authenticated-orcid":false,"given":"Ionela Daniela","family":"Morariu","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8147-3632","authenticated-orcid":false,"given":"Ancu\u021ba","family":"Lupu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1962-7861","authenticated-orcid":false,"given":"Gabriel","family":"Dascalescu","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, B-Dul Carol I, No. 11, 700506 Iasi, Romania"},{"name":"\u201cIoan Haulica\u201d Institute, Apollonia University, 700511 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2640-8795","authenticated-orcid":false,"given":"Vasile Valeriu","family":"Lupu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anton","family":"Knieling","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delia","family":"Nicolaiciuc","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alin","family":"Ciobica","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, B-Dul Carol I, No. 11, 700506 Iasi, Romania"},{"name":"\u201cIoan Haulica\u201d Institute, Apollonia University, 700511 Iasi, Romania"},{"name":"CENEMED Platform for Interdisciplinary Research, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Biomedical Research Group, \u201cOlga Necrasov\u201d Center, Romanian Academy, Iasi Branch, Teodor Codrescu 2, 700481 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena Andreea","family":"Chivasuta","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Department of Pathology, \u201cProf. Dr. Nicolae Oblu\u201d Emergency Clinical Hospital, 700309 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mihaela","family":"Tirnovanu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iurie","family":"Dondiuc","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, \u201cNicolae Testemitanu\u201d University of Medicine and Pharmacy, 2004 Chisinau, Moldova"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ciprian","family":"Ilea","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6530-6874","authenticated-orcid":false,"given":"Mihaela","family":"Grigore","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emil","family":"Anton","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nrc3181","article-title":"BRCA1 and BRCA2: Different roles in a common pathway of genome protection","volume":"12","author":"Roy","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0092-8674(02)00615-3","article-title":"Cancer susceptibility and the functions of BRCA1 and BRCA2","volume":"108","author":"Venkitaraman","year":"2002","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Abreu, R.B.V., Gomes, T.T., Nepomuceno, T.C., Li, X., Fuchshuber-Moraes, M., De Gregoriis, G., Suarez-Kurtz, G., Monteiro, A.N.A., and Carvalho, M.A. (2022). Functional Restoration of BRCA1 Nonsense Mutations by Aminoglycoside-Induced Readthrough. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.935995"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Elsakrmy, N., and Cui, H. (2023). R-Loops and R-Loop-Binding Proteins in Cancer Progression and Drug Resistance. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087064"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"28641","DOI":"10.1074\/jbc.M200748200","article-title":"BRCA1 facilitates microhomology-mediated end joining of DNA double strand breaks","volume":"277","author":"Zhong","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1126\/science.286.5442.1162","article-title":"Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks","volume":"286","author":"Cortez","year":"1999","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1158\/0008-5472.CAN-09-2850","article-title":"Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination","volume":"70","author":"Ransburgh","year":"2010","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1158\/0008-5472.CAN-05-2853","article-title":"BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants","volume":"66","author":"Elstrodt","year":"2006","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1158\/1055-9965.EPI-11-0775","article-title":"Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the Consortium of Investigators of Modifiers of BRCA1\/2 (CIMBA)","volume":"21","author":"Mavaddat","year":"2012","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.critrevonc.2006.01.006","article-title":"Histopathology of BRCA1- and BRCA2-associated breast cancer","volume":"59","author":"Honrado","year":"2006","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1093\/jnci\/92.7.564","article-title":"Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors","volume":"92","author":"Esteller","year":"2000","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1056\/NEJM200102223440801","article-title":"Gene-expression profiles in hereditary breast cancer","volume":"344","author":"Hedenfalk","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1126\/science.270.5237.789","article-title":"Aberrant subcellular localization of BRCA1 in breast cancer","volume":"270","author":"Chen","year":"1995","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/ng0396-303","article-title":"BRCA1 is secreted and exhibits properties of a granin","volume":"12","author":"Jensen","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/ng0697-122","article-title":"BRCA1 is localized in cytoplasmic tube-like invaginations in the nucleus","volume":"16","author":"Coene","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"32863","DOI":"10.1074\/jbc.271.51.32863","article-title":"The nuclear localization sequences of the BRCA1 protein interact with the importin-\u03b1 subunit of the nuclear transport signal receptor","volume":"271","author":"Chen","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S0092-8674(00)80503-6","article-title":"Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage","volume":"90","author":"Scully","year":"1997","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nmeth.3995","article-title":"A proposal for validation of antibodies","volume":"13","author":"Uhlen","year":"2016","journal-title":"Nat. Methods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e48363","DOI":"10.7554\/eLife.48363","article-title":"Implementation of an antibody characterization procedure and application to the major ALS\/FTD disease gene C9ORF72","volume":"8","author":"Laflamme","year":"2019","journal-title":"eLife"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s00428-012-1368-y","article-title":"Validation of the BRCA1 antibody MS110 and the utility of BRCA1 as a patient selection biomarker in immunohistochemical analysis of breast and ovarian tumours","volume":"462","author":"Milner","year":"2013","journal-title":"Virchows Arch."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/jcp.54.6.476","article-title":"The usefulness of antibodies to the BRCA1 protein in detecting the mutated BRCA1 gene. An immunohistochemical study","volume":"54","year":"2001","journal-title":"J. Clin. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mahmoud, A.M., Macias, V., Al-Alem, U., Deaton, R.J., Kadjaksy-Balla, A., Gann, P.H., and Rauscher, G.H. (2017). BRCA1 protein expression and subcellular localization in primary breast cancer: Automated digital microscopy analysis of tissue microarrays. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184385"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/6029","article-title":"Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas","volume":"21","author":"Wilson","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_24","first-page":"317","article-title":"p16 expression correlates with basal-like triple-negative breast carcinoma","volume":"7","author":"Eldweny","year":"2013","journal-title":"Ecancermedicalscience"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1002\/ijc.27316","article-title":"Cellular senescence and tumor suppressor gene p16","volume":"130","author":"Rayess","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1002\/(SICI)1097-0215(19980821)79:4<334::AID-IJC5>3.0.CO;2-W","article-title":"An important role for BRCA1 in breast cancer progression is indicated by its loss in a large proportion of non-familial breast cancers","volume":"79","author":"Taylor","year":"1998","journal-title":"Int. J. Cancer"},{"key":"ref_27","first-page":"1249","article-title":"Reduction of BRCA1 protein expression in Japanese sporadic breast carcinomas and its frequent loss in BRCA1-associated cases","volume":"5","author":"Yoshikawa","year":"1999","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/sj.onc.1201861","article-title":"BAP1: A novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression","volume":"16","author":"Jensen","year":"1998","journal-title":"Oncogene"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"23899","DOI":"10.1074\/jbc.C000276200","article-title":"The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin","volume":"275","author":"Bhattacharyya","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1083\/jcb.201004136","article-title":"A novel role for BRCA1 in regulating breast cancer cell spreading and motility","volume":"192","author":"Coene","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1056\/NEJMra1001389","article-title":"Triple-negative breast cancer","volume":"363","author":"Foulkes","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5232","DOI":"10.1038\/sj.onc.1202903","article-title":"Overexpression of BRCA2 gene in sporadic breast tumours","volume":"18","author":"Lidereau","year":"1999","journal-title":"Oncogene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/sj.bjc.6690722","article-title":"Detection of loss of heterozygosity at RAD51, RAD52, RAD54 and BRCA1 and BRCA2 loci in breast cancer: Pathological correlations","volume":"81","author":"Gonzalez","year":"1999","journal-title":"Br. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1158\/2159-8290.CD-18-1218","article-title":"PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer","volume":"9","author":"Pantelidou","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/nature23470","article-title":"Mitotic progression following DNA damage enables pattern recognition within micronuclei","volume":"548","author":"Harding","year":"2017","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Bodily, W.R., Shirts, B.H., Walsh, T., Gulsuner, S., King, M.C., Parker, A., Roosan, M., and Piccolo, S.R. (2020). Effects of germline and somatic events in candidate BRCA-like genes on breast-tumor signatures. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0239197"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Chen, H., Wu, J., Zhang, Z., Tang, Y., Li, X., Liu, S., Cao, S., and Li, X. (2018). Association Between BRCA Status and Triple-Negative Breast Cancer: A Meta-Analysis. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00909"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e18761429263841","DOI":"10.2174\/0118761429263841230926014118","article-title":"Deregulated MicroRNAs involved in P53 Signaling Pathway in Breast Cancer with Focus on Triple-negative Breast Cancer","volume":"17","author":"Naeimzadeh","year":"2023","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jconrel.2019.12.005","article-title":"Exosome-mediated siRNA delivery to suppress postoperative breast cancer metastasis","volume":"318","author":"Zhao","year":"2020","journal-title":"J. Control. Release Off. J. Control. Release Soc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1729\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T09:21:08Z","timestamp":1770801668000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1729"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,11]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27041729"],"URL":"https:\/\/doi.org\/10.3390\/ijms27041729","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,11]]}}}