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Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background:G protein-coupled receptor 19 (GPR19) is an orphan G protein-coupled receptor with emerging relevance in cancer; however, its role in breast cancer remains poorly understood. Given the high frequency of tumor protein p53 (TP53) alterations in aggressive breast cancer, particularly triple-negative breast cancer (TNBC), we investigated the clinical significance, biological function, and molecular mechanism of GPR19 in TP53-mutant breast cancer.Methods:Public datasets (Gene Expression Omnibus and The Cancer Genome Atlas) were analyzed to assess GPR19 expression in relation to TP53 status, molecular subtype, and prognosis. Expression was validated in breast cancer cell lines, paired clinical tissues, and tissue microarrays by quantitative PCR, Western blotting, immunofluorescence, and immunohistochemistry. Stable GPR19 knockdown models in MDA-MB-231 and BT-549 cells were used to evaluate proliferation, cell cycle distribution, and apoptosis. RNA sequencing, rescue experiments with the extracellular signal-regulated kinase (ERK) activator Ro 67-7476, and a nude mouse xenograft model were employed to investigate the underlying mechanism.Results:GPR19 was significantly upregulated in TP53-mutant breast cancer, primary tumors, and especially TNBC, and its high expression was associated with poor survival. Functionally, GPR19 depletion markedly suppressed cell proliferation, colony formation, and DNA synthesis, while inducing G2\/M arrest and apoptosis in TP53-mutant breast cancer cells. Mechanistically, GPR19 knockdown reduced ERK phosphorylation and downregulated forkhead box protein M1 (FOXM1) and its downstream G2\/M regulators cyclin B1 (CCNB1) and polo-like kinase 1 (PLK1), whereas total ERK levels remained largely unchanged. Pharmacological activation of ERK partially restored FOXM1 expression, alleviated cell cycle disturbance and apoptosis, and reversed the growth-inhibitory effects of GPR19 depletion. In vivo, GPR19 knockdown suppressed xenograft growth, reduced Ki-67 staining, increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) positivity, and inhibited the ERK\u2013FOXM1\u2013CCNB1\/PLK1 signaling cascade, all of which were partially rescued by ERK activation.Conclusions:GPR19 functions as a novel oncogenic driver and clinically relevant biomarker in breast cancer, particularly in TP53-mutant and TNBC subsets. By activating the ERK\u2013FOXM1 axis, GPR19 sustains cell cycle progression and suppresses apoptosis, highlighting this pathway as a potential therapeutic vulnerability in aggressive breast cancer.<\/jats:p>","DOI":"10.31083\/fbl52064","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:17:49Z","timestamp":1785413869000},"source":"Crossref","is-referenced-by-count":1,"title":["GPR19 Drives Cell Cycle Progression via ERK-Dependent FOXM1 Activation in p53-Mutant Breast Cancer"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8722-1426","authenticated-orcid":true,"given":"Jihan","family":"Qiu","sequence":"first","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2849-6343","authenticated-orcid":true,"given":"Cheng","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9860-508X","authenticated-orcid":true,"given":"Hanzhi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7225-470X","authenticated-orcid":true,"given":"Sumei","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2019-3623","authenticated-orcid":true,"given":"Chengcheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6128-3870","authenticated-orcid":true,"given":"Qiuyan","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8745-6493","authenticated-orcid":true,"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6539-170X","authenticated-orcid":true,"given":"Kuan","family":"He","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7736-510X","authenticated-orcid":true,"given":"Kang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4146-8369","authenticated-orcid":true,"given":"Yang","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Breast and 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