CdGAP is a talin-binding protein and a target of TGF-β signaling that promotes HER2-positive breast cancer growth and metastasis

Abstract

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.

Keywords: CP: Cancer; EMT; HER2-positive breast cancer; Rho GTPases; RhoGAP; TGF-β; cell invasion; integrin; metastasis; talin; tumorigenesis.