{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T18:29:51Z","timestamp":1768588191993,"version":"3.49.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Paired immunoglobulin-like type 2 receptor alpha (PILRA) is a membrane-associated receptor involved in immune regulation and signal transduction. However, its expression and functional role in breast cancer remain largely unknown. This study investigated the expression, mutation, and DNA methylation patterns of PILRA in breast cancer, along with its impact on immune infiltration and associated pathways. We also evaluated its potential as a therapeutic target for predicting prognosis and guiding immunotherapy in breast cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PILRA expression in breast cancer was analyzed using TCGA and GTEx datasets. Protein expression in breast cancer and adjacent normal tissues was evaluated by immunohistochemistry, and expression levels were validated by RT-qPCR in 50 paired tumor and adjacent tissue samples. cBioPortal was used to assess mutation profiles and prognostic relevance. Associations with drug resistance were examined by analyzing relationships to resistance- and sensitivity-related genes. DNA methylation and its prognostic impact were analyzed using MethSurv. The prognostic and diagnostic value of PILRA was evaluated through survival and ROC curve analyses. Single-cell and tissue expression data were obtained from HPA and GTEx, and gene effect score from DepMap. Immune associations were assessed using TISIDB. Gene correlation and protein-protein interaction networks were analyzed via TCGA and STRING, followed by KEGG and GO enrichment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PILRA expression was upregulated in breast cancer tissues and associated with poor survival and drug resistance. We identified R236M as the dominant mutation site and found that its mutation is linked to improved prognosis. PILRA methylation downregulated its expression and correlated with better prognosis. Survival analysis and ROC curves supported the potential of PILRA as a prognostic biomarker. PILRA was involved in immune infiltration and modulated the abundance of various immune cells and the tumor microenvironment, suggesting a role in immune regulation and tissue maintenance. Correlation and enrichment analyses revealed that PILRA-associated genes were mainly involved in cancer-related processes and pathways, with key hub genes in the PPI network.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We identified PILRA as a diagnostic and prognostic biomarker in breast cancer and analyzed its association with immunotherapy response. The findings provide new insight and potential strategies for breast cancer diagnosis and treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1682519","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T06:31:46Z","timestamp":1768545106000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["PILRA serves as a diagnostic and prognostic biomarker and modulates the tumor immune microenvironment and immunotherapy response in breast cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Bowen","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]},{"name":"Department of Cell Biology and Genetics, Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Genetics, Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junxia","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Genetics, Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3971\/j.issn.1000-8578.2012.04.011","article-title":"Clinical and pathological features and survival analysis of 178 triple-negative breast cancer cases","volume":"39","author":"Xiao","year":"2012","journal-title":"Zhong Liu Fang Zhi Yan Jiu"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2214\/AJR.17.18708","article-title":"Biomarkers and imaging of breast cancer","volume":"210","author":"Weaver","year":"2018","journal-title":"AJR Am J Roentgenol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12739","article-title":"The concept of immune surveillance against tumors","volume":"8","author":"Ribatti","year":"2017","journal-title":"first theories Oncotarget"},{"key":"B5","doi-asserted-by":"publisher","first-page":"85","DOI":"10.20053\/j.issn1001-5094.2024.02.002","article-title":"Mechanism and application progress of tumor immune markers in breast cancer immunotherapy","volume":"48","author":"Yang","year":"2024","journal-title":"Prog Pharm Sci"},{"key":"B6","doi-asserted-by":"publisher","first-page":"14334","DOI":"10.1038\/s41598-023-41649-6","article-title":"Comprehensive analysis of PILRA\u2019s association with the prognosis, tumor immune infiltration, and immunotherapy in pan-cancer","volume":"13","author":"Li","year":"2023","journal-title":"Sci Rep"},{"key":"B7","doi-asserted-by":"publisher","first-page":"13264","DOI":"10.1038\/s41598-022-17058-6","article-title":"PILRA polymorphism modifies the effect of APOE4 and GM17 on Alzheimer\u2019s disease risk","volume":"12","author":"Lopatko Lindman","year":"2022","journal-title":"Sci Rep"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2023.1082015","article-title":"PILRA is associated with immune cells infiltration in atrial fibrillation based on bioinformatics and experiment validation","volume":"10","author":"Shi","year":"2023","journal-title":"Front Cardiovasc Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1324105111","article-title":"Structural basis for simultaneous recognition of an O-glycan and its attached peptide of mucin family by immune receptor PILRA","volume":"111","author":"Kuroki","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.3.1197","article-title":"FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells","volume":"165","author":"Fournier","year":"2000","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201545897","article-title":"Monocyte infiltration into obese and fibrilized tissues is regulated by PILRA","volume":"46","author":"Kohyama","year":"2016","journal-title":"Eur J Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1126\/science.aaz8658","article-title":"The CD8\u03b1-PILRA interaction maintains CD8+ T cell quiescence","volume":"376","author":"Zheng","year":"2022","journal-title":"Science"},{"key":"B13","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/ni.2456","article-title":"Neutrophil infiltration during inflammation is regulated by PILRA via modulation of integrin activation","volume":"14","author":"Wang","year":"2013","journal-title":"Nat Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22052622","article-title":"TNMplot.com: A web tool for the comparison of gene expression in normal, tumor and metastatic tissues","volume":"22","author":"Bartha","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-0729","article-title":"KIR2DL2\/DL3+NKs and helios+Tregs in peripheral blood predict nivolumab response in patients with metastatic renal cell cancer","volume":"30","author":"Santagata","year":"2024","journal-title":"Clin Cancer Res"},{"key":"B17","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1186\/s12967-023-04419-6","article-title":"CD39 and LDHA affects the prognostic role of NLR in metastatic melanoma patients treated with immunotherapy","volume":"21","author":"Mallardo","year":"2023","journal-title":"J Transl Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25179345","article-title":"A combined proteomic and transcriptomic signature is predictive of response to anti-PD-1 treatment: a retrospective study in metastatic melanoma patients","volume":"25","author":"Mallardo","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-011315","article-title":"Gene-expression signature predicts autoimmune toxicity in metastatic melanoma","volume":"13","author":"Mallardo","year":"2025","journal-title":"J Immunother Cancer"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00037.2005","article-title":"Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system","volume":"86","author":"Sarkadi","year":"2006","journal-title":"Physiol Rev"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2004.06.022","article-title":"PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients","volume":"6","author":"Nagata","year":"2004","journal-title":"Cancer Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.379","article-title":"Acquired CDK6 amplification promotes breast cancer resistance to CDK4\/6 inhibitors and loss of ER signaling and dependence","volume":"36","author":"Yang","year":"2017","journal-title":"Oncogene"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-021-00773-4","article-title":"Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function","volume":"28","author":"Campbell","year":"2021","journal-title":"Cell Death Differ"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905833106","article-title":"MEK1 mutations confer resistance to MEK and B-RAF inhibition","volume":"106","author":"Emery","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B26","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/s41698-023-00360-5","article-title":"AKT\/mTOR signaling modulates resistance to endocrine therapy and CDK4\/6 inhibition in metastatic breast cancers","volume":"7","author":"Abu-Khalaf","year":"2023","journal-title":"NPJ Precis Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1813904","article-title":"Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer","volume":"380","author":"Andr\u00e9","year":"2019","journal-title":"N Engl J Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1348","article-title":"RAD51 mediates resistance of cancer stem cells to PARP inhibition in triple-negative breast cancer","volume":"23","author":"Liu","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2018.29","article-title":"Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges","volume":"15","author":"Fukumura","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1524-4741.2010.00903.x","article-title":"The clinical characteristics and prognosis of Chinese early stage breast cancer patients: a retrospective study","volume":"16","author":"Lu","year":"2010","journal-title":"Breast J"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3969\/j.issn.1000-8179.20150571","article-title":"Incidence, mortality and survival analysis of breast cancer in China","volume":"42","author":"Chen","year":"2015","journal-title":"Chin J Clin Oncol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1186\/s12885-016-2923-8","article-title":"ANLN is a prognostic biomarker independent of Ki-67 and essential for cell cycle progression in primary breast cancer","volume":"16","author":"Magnusson","year":"2016","journal-title":"BMC Cancer"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12082268","article-title":"Cyclin E2 promotes whole genome doubling in breast cancer","volume":"12","author":"Lee","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B34","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/s12935-020-01191-1","article-title":"Overexpression of kinesin superfamily members as prognostic biomarkers of breast cancer","volume":"20","author":"Li","year":"2020","journal-title":"Cancer Cell Int"},{"key":"B35","doi-asserted-by":"crossref","DOI":"10.1109\/ICBASE63199.2024.10762221","article-title":"Identification of prognostic biomarkers for stage III non-small cell lung carcinoma in female nonsmokers using machine learning","author":"Zheng","year":"2024"},{"key":"B36","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.molonc.2007.01.004","article-title":"Genetic and epigenetic alterations as biomarkers for cancer detection, diagnosis and prognosis","volume":"1","author":"Herceg","year":"2007","journal-title":"Mol Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2011.271","article-title":"Clinicopathological and prognostic implications of genetic alterations in oral cancers","volume":"2","author":"Pathare","year":"2011","journal-title":"Oncol Lett"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e39217","DOI":"10.7554\/eLife.39217","article-title":"Systematic identification of mutations and copy number alterations associated with cancer patient prognosis","volume":"7","author":"Smith","year":"2018","journal-title":"Elife"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.01.043","article-title":"PILRalpha is a herpes simplex virus-1 entry coreceptor that associates with glycoprotein B","volume":"132","author":"Satoh","year":"2008","journal-title":"Cell"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e1007427","DOI":"10.1371\/journal.pgen.1007427","article-title":"Paired immunoglobulin-like type 2 receptor alpha G78R variant alters ligand binding and confers protection to Alzheimer\u2019s disease","volume":"14","author":"Rathore","year":"2018","journal-title":"PloS Genet"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1682519\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T06:31:49Z","timestamp":1768545109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1682519\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,16]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2025.1682519"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1682519","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,16]]},"article-number":"1682519"}}