The tumor suppressor DACT3 sensitizes triple-negative breast cancer to apatinib by inhibiting the Wnt/β-catenin pathway

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-08-28 DOI:10.1016/j.tranon.2025.102509

Jing Wu , Rui Tian , Mei Liu , Yijing Liu , Bianfei Shao , Xiaohua Zeng

{"title":"The tumor suppressor DACT3 sensitizes triple-negative breast cancer to apatinib by inhibiting the Wnt/β-catenin pathway","authors":"Jing Wu , Rui Tian , Mei Liu , Yijing Liu , Bianfei Shao , Xiaohua Zeng","doi":"10.1016/j.tranon.2025.102509","DOIUrl":null,"url":null,"abstract":"<div><div>Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), shows efficient antitumor activity in heavily pretreated metastatic triple-negative breast cancer (TNBC). However, not all patients respond to apatinib, indicating that it is necessary to identify response biomarkers for more precise treatment and investigate the underlying mechanisms of apatinib resistance to develop new treatment strategies for TNBC. In this study, we identified the disheveled binding antagonist of beta-catenin 3 (DACT3) as a biomarker for apatinib sensitivity, as its expression level is significantly higher in apatinib-sensitive patients and positively correlates with longer survival. Furthermore, we explored that the exogenous expression of DACT3 could downregulate the IC<sub>50</sub> of apatinib (Vector vs DACT3: 16.04 μM vs 8.81 μM in MDA-MB231 cells, 19.65 μM vs 9.42 μM in YCCB1 cells) by inhibiting the Wnt/β-catenin signaling, a pro-malignancy pathway that leads to apatinib resistance through crosstalk with the VEGF/VEGFR2 pathway. In summary, our results indicate that DACT3 is a potential biomarker for predicting the response to apatinib and a new therapeutic target for improving TNBC sensitivity to apatinib.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"61 ","pages":"Article 102509"},"PeriodicalIF":5.0000,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Translational Oncology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1936523325002402","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Medicine","Score":null,"Total":0}

引用次数: 0

Abstract

Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), shows efficient antitumor activity in heavily pretreated metastatic triple-negative breast cancer (TNBC). However, not all patients respond to apatinib, indicating that it is necessary to identify response biomarkers for more precise treatment and investigate the underlying mechanisms of apatinib resistance to develop new treatment strategies for TNBC. In this study, we identified the disheveled binding antagonist of beta-catenin 3 (DACT3) as a biomarker for apatinib sensitivity, as its expression level is significantly higher in apatinib-sensitive patients and positively correlates with longer survival. Furthermore, we explored that the exogenous expression of DACT3 could downregulate the IC₅₀ of apatinib (Vector vs DACT3: 16.04 μM vs 8.81 μM in MDA-MB231 cells, 19.65 μM vs 9.42 μM in YCCB1 cells) by inhibiting the Wnt/β-catenin signaling, a pro-malignancy pathway that leads to apatinib resistance through crosstalk with the VEGF/VEGFR2 pathway. In summary, our results indicate that DACT3 is a potential biomarker for predicting the response to apatinib and a new therapeutic target for improving TNBC sensitivity to apatinib.

查看原文本刊更多论文

肿瘤抑制因子DACT3通过抑制Wnt/β-catenin通路使三阴性乳腺癌对阿帕替尼增敏

阿帕替尼是一种血管内皮生长因子受体2 （VEGFR2）的小分子抑制剂，在重度预处理的转移性三阴性乳腺癌（TNBC）中显示出有效的抗肿瘤活性。然而，并非所有患者都对阿帕替尼有反应，这表明有必要确定反应生物标志物以进行更精确的治疗，并研究阿帕替尼耐药的潜在机制，以制定新的TNBC治疗策略。在本研究中，我们确定了β -catenin 3的无序结合拮抗剂（disheveled binding antagonist of β -catenin 3, DACT3）作为阿帕替尼敏感性的生物标志物，因为它在阿帕替尼敏感患者中的表达水平明显更高，并且与更长的生存期呈正相关。此外，我们探索了外源表达DACT3可以通过抑制Wnt/β-catenin信号通路下调阿帕替尼的IC50（在MDA-MB231细胞中，Vector对DACT3: 16.04 μM vs 8.81 μM，在YCCB1细胞中，19.65 μM vs 9.42 μM）， Wnt/β-catenin信号通路是一种通过与VEGF/VEGFR2通路串串导致阿帕替尼耐药的促肿瘤通路。综上所述，我们的研究结果表明，DACT3是预测阿帕替尼反应的潜在生物标志物，也是提高TNBC对阿帕替尼敏感性的新治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.