上皮间质转变（Epithelial-to-mesenchymal transition, EMT）在转移中起着关键作用，转移是乳腺癌患者死亡的主要原因。在这里，我们展示了Cdc42 GTPase激活蛋白（CdGAP）促进了肿瘤形成和HER2阳性（HER2+）小鼠乳腺癌模型中向肺转移。CdGAP促进了作用于肺内、肺外穿过和在转移部位生长。在HER2+小鼠原发肿瘤中，CdGAP的减少介导了与Dlc1-RhoA通路的相互作用，并与转化生长因子β（TGF-β）诱导的EMT转录特征相联系。CdGAP在EMT期间通过TGF-β信号正调节，并与适配器talin相互作用以调节聚焦斑粘附动力学和整合素激活。此外，高CdGAP mRNA表达与高TGF-β-EMT特征结合的HER2+乳腺癌患者更容易出现淋巴结浸润。我们的结果表明，通过抑制TGF-β和整合素/talin信号通路，CdGAP可能是HER2+转移性乳腺癌的候选治疗靶点。 版权所有 © 2023 作者。由Elsevier Inc.出版。保留所有权利。

Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastasis, which is the leading cause of death in breast cancer patients. Here, we show that Cdc42 GTPase-activating protein (CdGAP) promotes tumor formation and metastasis to lungs in the HER2-positive (HER2+) murine breast cancer model. CdGAP facilitates intravasation, extravasation, and growth at metastatic sites. CdGAP depletion in HER2+ murine primary tumors mediates crosstalk with a Dlc1-RhoA pathway and is associated with a transforming growth factor β (TGF-β)-induced EMT transcriptional signature. CdGAP is positively regulated by TGF-β signaling during EMT and interacts with the adaptor talin to modulate focal adhesion dynamics and integrin activation. Moreover, HER2+ breast cancer patients with high CdGAP mRNA expression combined with a high TGF-β-EMT signature are more likely to present lymph node invasion. Our results suggest CdGAP as a candidate therapeutic target for HER2+ metastatic breast cancer by inhibiting TGF-β and integrin/talin signaling pathways.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.