{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:23:44Z","timestamp":1787649824638,"version":"build-2736575974"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Growing exposure to acetyl tributyl citrate (ATBC) drives breast cancer (BC) progression and poses significant challenges to clinical management. However, the precise molecular targets that mediate ATBC-induced tumor progression remain largely elusive. Identifying these cell surface and intracellular targets is critical for the development of rational, integrated targeted therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A comprehensive Network Toxicology approach combined with multi-omics bioinformatics was employed to elucidate the molecular targets of ATBC in BC. Core hub genes were identified by intersecting potential ATBC targets with BC-related differentially expressed genes (DEGs). The diagnostic and immunological significance of these targets was evaluated. Finally, molecular docking and\n                      <jats:italic>in vitro<\/jats:italic>\n                      functional assays on BC cell lines were performed to validate target engagement and therapeutic potential.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ATBC exposure demonstrated potential carcinogenic risk and promoted BC progression. We identified three critical hub targets:\n                      <jats:italic>EGFR<\/jats:italic>\n                      ,\n                      <jats:italic>MMP9<\/jats:italic>\n                      , and\n                      <jats:italic>AGTR1<\/jats:italic>\n                      . Molecular docking confirmed high binding affinities between ATBC and these target proteins.\n                      <jats:italic>In vitro<\/jats:italic>\n                      validation revealed that ATBC significantly promoted cell proliferation and migration, and suppressed apoptosis in ER-positive MCF-7 cells, a mechanism driven by profound upregulation of\n                      <jats:italic>EGFR<\/jats:italic>\n                      ,\n                      <jats:italic>MMP9<\/jats:italic>\n                      , and\n                      <jats:italic>AGTR1<\/jats:italic>\n                      mRNA expression. Furthermore, the expression of these targets correlated significantly with immune cell infiltration within the tumor microenvironment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      ATBC may promote BC progression through upregulation of\n                      <jats:italic>EGFR<\/jats:italic>\n                      ,\n                      <jats:italic>MMP9<\/jats:italic>\n                      , and\n                      <jats:italic>AGTR1<\/jats:italic>\n                      . These genes represent both potential diagnostic biomarkers and actionable therapeutic targets, providing a rational basis for repurposing existing\n                      <jats:italic>EGFR<\/jats:italic>\n                      inhibitors and angiotensin receptor blockers to treat environmentally driven BC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1896118","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:05:48Z","timestamp":1787648748000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of EGFR, MMP9, and AGTR1 as actionable therapeutic targets in acetyl tributyl citrate-driven breast cancer: integrated network toxicology and in vitro validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Bo","family":"Zhou","sequence":"first","affiliation":[{"name":"Taishan Academy of Medical Sciences, The Affiliated Taian City Central Hospital of Qingdao University","place":["Taian, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Esophageal and Gastrointestinal Oncology, The Affiliated Taian City Central Hospital of Qingdao University","place":["Taian, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Outpatient Department, The Affiliated Taian City Central Hospital of Qingdao University","place":["Taian, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyang","family":"An","sequence":"additional","affiliation":[{"name":"Department of General Obstetrics, The Affiliated Taian City Central Hospital of Qingdao University","place":["Taian, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"834","DOI":"10.3390\/cells12060834","article-title":"Bioinformatic miRNA-mRNAs analysis revels to miR-934 as a potential regulator of the epithelial\u2013mesenchymal transition in triple-negative breast cancer","volume":"12","author":"Contreras-Rodr\u00edguez","year":"2023","journal-title":"Cells"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2761","DOI":"10.1158\/0008-5472.can-23-2526","article-title":"Obesity induces temporally regulated alterations in the extracellular matrix that drive breast tumor invasion and metastasis","volume":"84","author":"Conner","year":"2024","journal-title":"Cancer Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"117876","DOI":"10.1016\/j.ecoenv.2025.117876","article-title":"The efficient prediction of inflammatory osteolysis caused by polylactic acid through network toxicology and molecular docking strategy","volume":"291","author":"Cui","year":"2025","journal-title":"Ecotoxicol. 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