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

IF 3.7 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY IUBMB Life Pub Date : 2025-01-16 DOI:10.1002/iub.2940
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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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.

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Tinagl1通过同时阻断他莫昔芬耐药乳腺癌细胞中的EGFR和β1-整合素/FAK信号通路,恢复他莫昔芬敏感性并阻断纤维连接素诱导的EMT。
三苯氧胺(Tamoxifen, TAM)用于治疗绝经前er阳性乳腺癌患者,TAM耐药是影响其疗效的主要原因。因此,解决TAM耐药性对改善治疗效果至关重要。这项研究探索了分泌的细胞外基质蛋白Tinagl1的潜在作用,其表达在tam耐药的MCF-7乳腺癌细胞(MCF-7R)中受损。我们发现,Tinagl1通过抑制EGFR和β1-整合素/局灶粘附激酶(FAK)信号通路,在对抗TAM耐药中发挥关键作用,这两种信号通路在MCF-7R细胞中都异常激活,并参与耐药机制。我们的数据显示,与野生型细胞相比,MCF-7R细胞中Tinagl1的表达水平较低,TAM可以进一步降低MCF-7R细胞中Tinagl1的表达,这与我们的芯片结果一致。此外,在体外和体内实验中,Tinagl1可以通过调节上皮-间质转化(epithelial-mesenchymal transition, EMT),恢复MCF-7R细胞对TAM的敏感性,抑制MCF-7R细胞的运动。此外,tam耐药乳腺癌样本中的Tinagl1水平明显低于与其匹配的原发肿瘤。在线数据库的分析进一步表明,高Tinagl1表达与更好的无复发生存(RFS)相关,特别是在er阳性,her2阴性乳腺癌患者中。总的来说,这项研究不仅将Tinagl1定位为潜在的预后标志物,而且作为一个有希望的治疗靶点。
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来源期刊
IUBMB Life
IUBMB Life 生物-生化与分子生物学
CiteScore
10.60
自引率
0.00%
发文量
109
审稿时长
4-8 weeks
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.
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