{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:02:33Z","timestamp":1789984953388,"version":"4.0.1"},"reference-count":28,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive subtype with limited therapeutic targets. We retrospectively evaluated the expression of phosphatase and tensin homolog (PTEN) and transmembrane serine protease 4 (TMPRSS4) by immunohistochemistry in formalin-fixed, paraffin-embedded tumor tissues from 145 patients with histologically confirmed TNBC, and we analyzed associations with clinicopathological features, Fudan immunohistochemistry-based subtypes, and clinical outcomes. Clinicopathological analyses included all 145 cases. Exploratory survival analyses included 59 patients with complete, verifiable follow-up and outcome data (median follow-up, 46 months), during which three deaths and eight progression events occurred. PTEN-retained expression was associated with worse overall survival (OS; log-rank p = 0.030), whereas TMPRSS4-positive expression was associated with worse progression-free survival (PFS; log-rank p = 0.034). TMPRSS4 expression showed a nominal association with Fudan subtype in the unadjusted omnibus analysis (p = 0.025), which was considered exploratory after Benjamini\u2013Hochberg correction (q = 0.379). The PTEN and TMPRSS4 staining categories were not significantly associated. In an exploratory four-group survival analysis, patients with concurrent PTEN-retained and TMPRSS4-positive expression (PTEN+\/TMPRSS4+) showed the lowest OS and PFS estimates, patients with PTEN loss and TMPRSS4 negativity (PTEN\u2212\/TMPRSS4\u2212) showed the highest estimates, and the two single-positive groups showed intermediate estimates. Independent transcript-level validation restricted to TNBC in The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) did not reproduce these protein-level associations. These protein-level findings should therefore be considered exploratory and hypothesis-generating and warrant confirmation in larger, adequately powered cohorts using standardized immunohistochemistry with complete treatment data.<\/jats:p>","DOI":"10.3390\/life16091563","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1563","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Associations of PTEN and TMPRSS4 Expression with Clinical Outcomes and Fudan Immunohistochemistry-Based Subtypes in Triple-Negative Breast Cancer"],"prefix":"10.3390","volume":"16","author":[{"given":"Wei","family":"Hou","sequence":"first","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianbin","family":"Wei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinting","family":"Diao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7239-2360","authenticated-orcid":false,"given":"Yiqiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Xiuli","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","first-page":"394","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13058-020-01296-5","article-title":"Triple-negative breast cancer molecular subtyping and treatment progress","volume":"22","author":"Yin","year":"2020","journal-title":"Breast Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.ccell.2019.02.001","article-title":"Genomic and transcriptomic landscape of triple-negative breast cancers: Subtypes and treatment strategies","volume":"35","author":"Jiang","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41571-021-00565-2","article-title":"Treatment landscape of triple-negative breast cancer\u2014Expanded options, evolving needs","volume":"19","author":"Bianchini","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Nedeljkovic, J., and Damjanovic, A. (2019). Mechanisms of chemotherapy resistance in triple-negative breast cancer\u2014How we can rise to the challenge. Cells, 8.","DOI":"10.3390\/cells8090957"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s12282-024-01567-5","article-title":"PI3K\/AKT\/mTOR signaling pathway: An important driver and therapeutic target in triple-negative breast cancer","volume":"31","author":"Zhang","year":"2024","journal-title":"Breast Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/nrm3330","article-title":"The functions and regulation of the PTEN tumour suppressor","volume":"13","author":"Song","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6084","DOI":"10.1158\/0008-5472.CAN-07-6854","article-title":"An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer","volume":"68","author":"Lluch","year":"2008","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1146\/annurev.pathol.4.110807.092311","article-title":"PTEN and the PI3-kinase pathway in cancer","volume":"4","author":"Chalhoub","year":"2009","journal-title":"Annu. Rev. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/s12276-023-00975-5","article-title":"TMPRSS4, a type II transmembrane serine protease, as a potential therapeutic target in cancer","volume":"55","author":"Kim","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/bjc.2014.403","article-title":"TMPRSS4: An emerging potential therapeutic target in cancer","volume":"112","author":"Calvo","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"76327","DOI":"10.18632\/oncotarget.10153","article-title":"TMPRSS4 as an emerging potential poor prognostic factor for solid tumors: A systematic review and meta-analysis","volume":"7","author":"Zeng","year":"2016","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1038\/sj.onc.1210914","article-title":"TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial\u2013mesenchymal transition","volume":"27","author":"Jung","year":"2008","journal-title":"Oncogene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1158\/1078-0432.CCR-14-2993","article-title":"PTEN loss is associated with worse outcome in HER2-amplified breast cancer patients but is not associated with trastuzumab resistance","volume":"21","author":"Stern","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e1481","DOI":"10.1634\/theoncologist.2019-0982","article-title":"Molecular subtyping of triple-negative breast cancers by immunohistochemistry: Molecular basis and clinical relevance","volume":"25","author":"Zhao","year":"2020","journal-title":"Oncologist"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13375","DOI":"10.1074\/jbc.273.22.13375","article-title":"The tumor suppressor, PTEN\/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate","volume":"273","author":"Maehama","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0092-8674(00)81780-8","article-title":"Negative regulation of PKB\/Akt-dependent cell survival by the tumor suppressor PTEN","volume":"95","author":"Stambolic","year":"1998","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Network (2012). Comprehensive molecular portraits of human breast tumours. Nature, 490, 61\u201370.","DOI":"10.1038\/nature11412"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s10549-015-3430-3","article-title":"Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer","volume":"151","author":"Beg","year":"2015","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13058-019-1098-z","article-title":"A subgroup of microRNAs defines PTEN-deficient, triple-negative breast cancer patients with poorest prognosis and alterations in RB1, MYC, and Wnt signaling","volume":"21","author":"Wang","year":"2019","journal-title":"Breast Cancer Res."},{"key":"ref_22","first-page":"65566","article-title":"Loss of PTEN expression in breast cancer: Association with clinicopathological characteristics and prognosis","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1158\/1055-9965.EPI-22-0672","article-title":"Loss of PTEN Expression, PIK3CA Mutations, and Breast Cancer Survival in the Nurses\u2019 Health Studies","volume":"31","author":"Wang","year":"2022","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"927","DOI":"10.3892\/ijmm.2017.2893","article-title":"Overexpression of TMPRSS4 promotes tumor proliferation and aggressiveness in breast cancer","volume":"39","author":"Li","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1111\/bph.15218","article-title":"Ribosomes as a nexus between translation and cancer progression: Focus on ribosomal receptor for activated C kinase 1 (RACK1) in breast cancer","volume":"179","author":"Buoso","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/s41389-020-00291-x","article-title":"OXER1 and RACK1-associated pathway: A promising drug target for breast cancer progression","volume":"9","author":"Masi","year":"2020","journal-title":"Oncogenesis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/s41388-024-03224-9","article-title":"Unveiling RACK1: A key regulator of the PI3K\/AKT pathway in prostate cancer development","volume":"44","author":"Lyu","year":"2025","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.phrs.2019.03.008","article-title":"Cortisol-induced SRSF3 expression promotes GR splicing, RACK1 expression and breast cancer cells migration","volume":"143","author":"Buoso","year":"2019","journal-title":"Pharmacol. Res."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/9\/1563\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:30:02Z","timestamp":1789983002000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/9\/1563"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":28,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["life16091563"],"URL":"https:\/\/doi.org\/10.3390\/life16091563","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]}}}