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This study explored the potential role of Tinagl1, a secreted extracellular matrix protein, whose expression is compromised in TAM\u2010resistant MCF\u20107 breast cancer cells (MCF\u20107R). We discovered that Tinagl1 plays a pivotal role in countering TAM resistance by inhibiting the EGFR and \u03b21\u2010integrin\/focal adhesion kinase (FAK) signaling pathways, both of which are abnormally activated in MCF\u20107R cells and contribute to the resistance mechanism. Our data showed that the expression level of Tinagl1 in MCF\u20107R cells was lower compared to their wild\u2010type counterparts, and TAM could further reduce Tinagl1 expression in MCF\u20107R cells, which was consistent with our microarray results. Moreover, Tinagl1 could restore the sensitivity of MCF\u20107R cells to TAM and inhibit the motility of MCF\u20107R cells by regulating epithelial\u2010mesenchymal transition (EMT) in vitro and in vivo experiments. In addition, the level of Tinagl1 in TAM\u2010resistant breast cancer samples was significantly lower than that in their matched primary tumors. Analysis of an online database further indicated that high Tinagl1 expression correlates with better recurrence\u2010free survival (RFS), particularly in patients with ER\u2010positive, HER2\u2010negative breast cancer. Overall, this study positions Tinagl1 not only as a potential prognostic marker but also as a promising therapeutic target.<\/jats:p>","DOI":"10.1002\/iub.2940","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T13:01:30Z","timestamp":1737032490000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Tinagl1 restores tamoxifen sensitivity and blocks fibronectin\u2010induced <scp>EMT<\/scp> by simultaneously blocking the <scp>EGFR<\/scp> and \u03b21\u2010integrin\/<scp>FAK<\/scp> signaling pathways in tamoxifen\u2010resistant breast cancer cells"],"prefix":"10.1002","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5209-3874","authenticated-orcid":false,"given":"Jie","family":"Yuan","sequence":"first","affiliation":[{"name":"Department of General Surgery, Beijing Anzhen Hospital Capital Medical University  Beijing China"},{"name":"Department of Breast, Thyroid and 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