Tinagl1 restores tamoxifen sensitivity and blocks fibronectin-induced EMT by simultaneously blocking the EGFR and β1-integrin/FAK signaling pathways in tamoxifen-resistant breast cancer cells
Jie Yuan, Li Yuan, Li Yang, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Jun Huang, Bei Wang, Shuqi Zhang, Changsheng Wei, Chengyu Luo
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引用次数: 0
Abstract
Tamoxifen (TAM) is employed to treat premenopausal ER-positive breast cancer patients, but TAM resistance is the main reason affecting its efficacy. Thus, addressing TAM resistance is crucial for improving therapeutic outcomes. This study explored the potential role of Tinagl1, a secreted extracellular matrix protein, whose expression is compromised in TAM-resistant MCF-7 breast cancer cells (MCF-7R). We discovered that Tinagl1 plays a pivotal role in countering TAM resistance by inhibiting the EGFR and β1-integrin/focal adhesion kinase (FAK) signaling pathways, both of which are abnormally activated in MCF-7R cells and contribute to the resistance mechanism. Our data showed that the expression level of Tinagl1 in MCF-7R cells was lower compared to their wild-type counterparts, and TAM could further reduce Tinagl1 expression in MCF-7R cells, which was consistent with our microarray results. Moreover, Tinagl1 could restore the sensitivity of MCF-7R cells to TAM and inhibit the motility of MCF-7R cells by regulating epithelial-mesenchymal transition (EMT) in vitro and in vivo experiments. In addition, the level of Tinagl1 in TAM-resistant 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-free survival (RFS), particularly in patients with ER-positive, HER2-negative breast cancer. Overall, this study positions Tinagl1 not only as a potential prognostic marker but also as a promising therapeutic target.
期刊介绍:
IUBMB Life is the flagship journal of the International Union of Biochemistry and Molecular Biology and is devoted to the rapid publication of the most novel and significant original research articles, reviews, and hypotheses in the broadly defined fields of biochemistry, molecular biology, cell biology, and molecular medicine.