A trafficking regulatory subnetwork governs a_Vß₆ integrin-HER2 cross-talk to control breast cancer invasion and drug resistance

HER2 and alpha V beta 6 integrin are independent predictors of breast cancer survival and metastasis. We identify an alpha V beta 6/HER2 cross-talk mechanism driving invasion, which is dysregulated in drug-resistant HER2+ breast cancer cells. Proteomic analyses reveal ligand-bound alpha V beta 6 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 alpha V beta 6 and HER2, affecting receptor trafficking and signaling. Acute exposure to trastuzumab increases recruitment of the subnetwork to alpha V beta 6, but trastuzumab resistance decouples GDI2 recruitment. GDI2, RAB5, and RAB7A cooperate to regulate migration and transforming growth factor-beta activation to promote invasion. However, these mechanisms are dysregulated in trastuzumab-resistant cells. In patients, RAB5A, RAB7A, and GDI2 expression correlates with patient survival and alpha V beta 6 expression predicts relapse following trastuzumab treatment. Thus, the RAB5/RAB7A/GDI2 subnetwork regulates alpha V beta 6-HER2 cross-talk to drive breast cancer invasion but is subverted in trastuzumab-resistant cells to drive alpha V beta 6-independent and HER2-independent tumor progression.