A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance

HER2 and α β integrin are independent predictors of breast cancer survival and metastasis. We identify an α β /HER2 cross-talk mechanism driving invasion, which is dysregulated in drug-resistant HER2+ breast cancer cells. Proteomic analyses reveal ligand-bound α β recruits HER2 and a trafficking subnetwork, comprising guanosine triphosphatases RAB5 and RAB7A and the Rab regulator guanine nucleotide dissociation inhibitor 2 (GDI2). The RAB5/RAB7A/GDI2 functional module mediates direct cross-talk between α β and HER2, affecting receptor trafficking and signaling. Acute exposure to trastuzumab increases recruitment of the subnetwork to α β , but trastuzumab resistance decouples GDI2 recruitment. GDI2, RAB5, and RAB7A cooperate to regulate migration and transforming growth factor-β activation to promote invasion. However, these mechanisms are dysregulated in trastuzumab-resistant cells. In patients, , , and expression correlates with patient survival and α β expression predicts relapse following trastuzumab treatment. Thus, the RAB5/RAB7A/GDI2 subnetwork regulates α β -HER2 cross-talk to drive breast cancer invasion but is subverted in trastuzumab-resistant cells to drive α β -independent and HER2-independent tumor progression.