CdGAP is a talin-binding protein and a target of TGF-β signaling that promotes HER2-positive breast cancer growth and metastasis
Yi He,
Marie-Anne Goyette,
Jennifer Chapelle,
Nadia Boufaied,
Jalal Al Rahbani,
Maribel Schonewolff,
Eric I. Danek,
William J. Muller,
David P. Labbé,
Jean-François Côté,
Nathalie Lamarche-Vane
Affiliations
Yi He
Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
Marie-Anne Goyette
Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, QC H2W 1R7, Canada
Jennifer Chapelle
Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
Nadia Boufaied
Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
Jalal Al Rahbani
Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
Maribel Schonewolff
Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
Eric I. Danek
Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
William J. Muller
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada
David P. Labbé
Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada; Division of Urology, Department of Surgery, McGill University, Montréal, QC H4A 3J1, Canada
Jean-François Côté
Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada; Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, QC H2W 1R7, Canada
Nathalie Lamarche-Vane
Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada; Corresponding author
Summary: 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.
