{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T05:19:08Z","timestamp":1787548748779,"version":"build-2736575974"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>This study aims to systematically elucidate the clinical significance and biological function of the phospholipid phosphatase (PLPP) family member (PPAP2C) phosphatidic acid phosphatase type 2C in breast cancer, and to evaluate its potential as a prognostic biomarker and therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Gene expression data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases were integrated to characterize the expression profile of PLPP family members, focusing on PPAP2C in breast cancer. The prognostic value of PPAP2C, initially identified at the mRNA level (TCGA, (METABRIC) Molecular Taxonomy of Breast Cancer International Consortium, Gene Expression Omnibus (GEO)), was confirmed at the protein level by immunohistochemistry (IHC) on tissue microarrays (TMA). The oncogenic functions of PPAP2C were investigated in triple-negative breast cancer (TNBC) cells through CRISPR-Cas9-mediated knockout and ectopic overexpression, with assessment of key phenotypes including proliferation, colony formation, migration, and invasion.\n                      <jats:italic>In vivo<\/jats:italic>\n                      validation was subsequently performed using an MDA-MB-231 xenograft model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      PPAP2C exhibits the most significant overexpression pattern across 33 cancer types (upregulated in 16 cancers, downregulated in only 3). Compared with normal tissues, PPAP2C showed specific overexpression in breast cancer tissues and was significantly associated with advanced clinical stages and aggressive subtypes (HER2\n                      <jats:sup>+<\/jats:sup>\n                      and TNBC). Survival analysis demonstrated that high PPAP2C expression correlated with significantly shorter overall survival and disease-free survival, which was further validated in METABRIC and GEO cohorts. Tissue microarray analysis confirmed higher PPAP2C protein positivity in tumor tissues (94.7%) than in adjacent normal tissues (59.7%), with worse OS and RFS in high-expression groups. Multivariate analysis identified PPAP2C as an independent prognostic factor for OS. Functional experiments revealed that PPAP2C knockout (via 5-bp\/1-bp frameshift mutations) suppressed TNBC cell proliferation, colony formation, migration, and invasion, while overexpression enhanced these phenotypes.\n                      <jats:italic>In vivo<\/jats:italic>\n                      studies further demonstrated complete tumor regression in MDA-MB-231 xenografts upon PPAP2C knockout.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study identifies PPAP2C as a key oncogenic driver and a robust independent prognostic biomarker in breast cancer. The findings provide compelling evidence that PPAP2C represents a promising therapeutic target, offering a new strategic avenue for precision therapy, particularly for aggressive breast cancer subtypes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1884232","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T04:24:38Z","timestamp":1787545478000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated multi-omics analysis and functional experiments reveals PPAP2C as a potential prognostic biomarker and therapeutic target in breast cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaoxi","family":"Lin","sequence":"first","affiliation":[{"name":"Chifeng Municipal Hospital, Chifeng Clinical Medical School, Inner Mongolia Medical University","place":["Chifeng, Inner Mongolia, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihang","family":"Cen","sequence":"additional","affiliation":[{"name":"Liuzhou Key Laboratory of Cancer Biotherapy, Liuzhou Municipal Liutie Central Hospital, Affiliated Liuzhou Hospital of Youjiang Medical University for Nationalities","place":["Liuzhou, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sihui","family":"Yue","sequence":"additional","affiliation":[{"name":"Chifeng Municipal Hospital, Chifeng Clinical Medical School, Inner Mongolia Medical University","place":["Chifeng, Inner Mongolia, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangsen","family":"Teng","sequence":"additional","affiliation":[{"name":"Liuzhou Key Laboratory of Cancer Biotherapy, Liuzhou Municipal Liutie Central Hospital, Affiliated Liuzhou Hospital of Youjiang Medical University for Nationalities","place":["Liuzhou, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Qin","sequence":"additional","affiliation":[{"name":"Liuzhou Key Laboratory of Cancer Biotherapy, Liuzhou Municipal Liutie Central Hospital, Affiliated Liuzhou Hospital of Youjiang Medical University for Nationalities","place":["Liuzhou, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yipeng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Chifeng Municipal Hospital, Chifeng Clinical Medical School, Inner Mongolia Medical University","place":["Chifeng, Inner Mongolia, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyue","family":"Qiu","sequence":"additional","affiliation":[{"name":"Chifeng Municipal Hospital, Chifeng Clinical Medical School, Inner Mongolia Medical University","place":["Chifeng, Inner Mongolia, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggang","family":"Lu","sequence":"additional","affiliation":[{"name":"Liuzhou Key Laboratory of Cancer Biotherapy, Liuzhou Municipal Liutie Central Hospital, Affiliated Liuzhou Hospital of Youjiang Medical University for Nationalities","place":["Liuzhou, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Liuzhou Key Laboratory of Cancer Biotherapy, Liuzhou Municipal Liutie Central Hospital, Affiliated Liuzhou Hospital of Youjiang Medical University for Nationalities","place":["Liuzhou, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuguang","family":"Zuo","sequence":"additional","affiliation":[{"name":"Liuzhou Key Laboratory of Cancer Biotherapy, Liuzhou Municipal Liutie Central Hospital, Affiliated Liuzhou Hospital of Youjiang Medical University for Nationalities","place":["Liuzhou, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7257","DOI":"10.1073\/pnas.1001529107","article-title":"Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation","volume":"107","author":"Albers","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2299","DOI":"10.3390\/cancers15082299","article-title":"Decreased lipid phosphate phosphatase 1\/3 and increased lipid phosphate phosphatase 2 expression in the human breast cancer tumor microenvironment promotes tumor progression and immune system evasion","volume":"15","author":"Benesch","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B3","doi-asserted-by":"publisher","first-page":"7165","DOI":"10.1158\/0008-5472.CAN-08-1360","article-title":"Characterization of the recurrent 8p11-12 amplicon identifies PPAPDC1B, a phosphatase protein, as a new therapeutic target in breast cancer","volume":"68","author":"Bernard-Pierrot","year":"2008","journal-title":"Cancer Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"9643","DOI":"10.1073\/pnas.0600979103","article-title":"The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases","volume":"103","author":"Boucharaba","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B5","doi-asserted-by":"publisher","first-page":"24281","DOI":"10.1074\/jbc.273.38.24281","article-title":"Mammalian lipid phosphate phosphohydrolases","volume":"273","author":"Brindley","year":"1998","journal-title":"J. Biol. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1016\/j.bbalip.2009.02.007","article-title":"Phosphatidate degradation: phosphatidate phosphatases (lipins) and lipid phosphate phosphatases","volume":"1791","author":"Brindley","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"B7","doi-asserted-by":"publisher","first-page":"eabo0264","DOI":"10.1126\/scisignal.abo0264","article-title":"Overarching roles of diacylglycerol signaling in cancer development and antitumor immunity","volume":"15","author":"Cooke","year":"2022","journal-title":"Sci. Signal"},{"key":"B8","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1158\/1535-7163.MCT-08-0636","article-title":"Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets","volume":"8","author":"Flanagan","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.2147\/BCTT.S553681","article-title":"Integrated pan-cancer profiling and breast cancer validation identify BEND3 as a potential prognostic and immune biomarker","volume":"17","author":"Gou","year":"2025","journal-title":"Breast Cancer (Dove Med. Press)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"650","DOI":"10.3390\/cancers17040650","article-title":"Lipid metabolism in breast cancer: from basic research to clinical application","volume":"17","author":"Huang","year":"2025","journal-title":"Cancers (Basel)"},{"key":"B11","doi-asserted-by":"publisher","first-page":"9575","DOI":"10.3390\/ijms22179575","article-title":"Autotaxin-LPA-LPP3 axis in energy metabolism and metabolic disease","volume":"22","author":"Jose","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"231418","DOI":"10.1155\/2014\/231418","article-title":"Protein kinase C (PKC) isozymes and cancer","volume":"2014","author":"Kang","year":"2014","journal-title":"New J. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1038\/s41586-025-09812-3","article-title":"Whole-genome landscapes of 1,364 breast cancers","volume":"649","author":"Kim","year":"2026","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1042\/bj20051674","article-title":"Lipid phosphate phosphatase-1 regulates lysophosphatidic acid- and platelet-derived-growth-factor-induced cell migration","volume":"394","author":"Long","year":"2006","journal-title":"Biochem. J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1038\/nrc1143","article-title":"The emerging role of lysophosphatidic acid in cancer","volume":"3","author":"Mills","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"B16","doi-asserted-by":"publisher","first-page":"9297","DOI":"10.1074\/jbc.M511710200","article-title":"Lipid phosphate phosphatase-2 activity regulates S-phase entry of the cell cycle in Rat2 fibroblasts","volume":"281","author":"Morris","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"L1","DOI":"10.1152\/ajplung.00029.2002","article-title":"Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase","volume":"284","author":"Nanjundan","year":"2003","journal-title":"Am. J. Physiol. Lung Cell. Molecul. Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.bbalip.2012.07.012","article-title":"Lipid phosphate phosphatase (LPP3) and vascular development","volume":"1831","author":"Ren","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"B19","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.3390\/biom10091263","article-title":"Lipid phosphate phosphatases and cancer","volume":"10","author":"Tang","year":"2020","journal-title":"Biomolecules"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2389","DOI":"10.1194\/jlr.M053462","article-title":"Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice","volume":"55","author":"Tang","year":"2014","journal-title":"J. Lipid Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2048","DOI":"10.1194\/jlr.R058362","article-title":"Lipid phosphate phosphatases and their roles in Mammalian physiology and pathology","volume":"56","author":"Tang","year":"2015","journal-title":"J. Lipid Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"5675","DOI":"10.7150\/thno.66230","article-title":"Lipid phosphate phosphatase-2 promotes tumor growth through increased c-Myc expression","volume":"12","author":"Tang","year":"2022","journal-title":"Theranostics"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3534","DOI":"10.1158\/1078-0432.CCR-03-0069","article-title":"Role of decreased levels of lipid phosphate phosphatase-1 in accumulation of lysophosphatidic acid in ovarian cancer","volume":"9","author":"Tanyi","year":"","journal-title":"Clin. Cancer Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1158\/0008-5472.CAN-02-1986","article-title":"The human lipid phosphate phosphatase-3 decreases the growth, survival, and tumorigenesis of ovarian cancer cells: validation of the lysophosphatidic acid signaling cascade as a target for therapy in ovarian cancer","volume":"63","author":"Tanyi","year":"","journal-title":"Cancer Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/s12943-025-02258-1","article-title":"Lipid metabolic reprograming: the unsung hero in breast cancer progression and tumor microenvironment","volume":"24","author":"Wan","year":"2025","journal-title":"Mol. Cancer"},{"key":"B27","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1186\/s13046-023-02877-w","article-title":"Transcriptomic landscape based on annotated clinical features reveals PLPP2 involvement in lipid raft-mediated proliferation signature of early-stage lung adenocarcinoma","volume":"42","author":"Wang","year":"2023","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.7150\/ijbs.92125","article-title":"Reprogramming of lipid metabolism mediates crosstalk, remodeling, and intervention of microenvironment components in breast cancer","volume":"20","author":"Wang","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1770711","DOI":"10.3389\/fimmu.2026.1770711","article-title":"The value of protein phosphatase methylesterase 1 in diagnosis, prognosis and immunoregulation: from pan-cancer analysis to breast cancer verification","volume":"17","author":"Wang","year":"2026","journal-title":"Front. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.3390\/cancers11101523","article-title":"Targeting lysophosphatidic acid in cancer: the issues in moving from bench to bedside","volume":"11","author":"Xu","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"177202","DOI":"10.1016\/j.ejphar.2024.177202","article-title":"Advancements in clinical research and emerging therapies for triple-negative breast cancer treatment","volume":"988","author":"Xu","year":"2025","journal-title":"Eur. J. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s12943-017-0717-5","article-title":"Phospholipid phosphatase 4 promotes proliferation and tumorigenesis, and activates Ca(2+)-permeable cationic channel in lung carcinoma cells","volume":"16","author":"Zhang","year":"2017","journal-title":"Mol. Cancer"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1884232\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T04:24:39Z","timestamp":1787545479000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1884232\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":32,"alternative-id":["10.3389\/fphar.2026.1884232"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1884232","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,24]]},"article-number":"1884232"}}