The type III TGF-β receptor suppresses breast cancer progression through GIPC-mediated inhibition of TGF-β signaling

Loss of expression of the type III transforming growth factor-beta receptor (T beta RIII or betaglycan), a transforming growth factor-beta (TGF-beta) superfamily co-receptor, is common in human breast cancers. T beta RIII suppresses cancer progression in vivo by reducing cancer cell migration and invasion by largely unknown mechanisms. Here, we demonstrate that the cytoplasmic domain of T beta RIII is essential for T beta RIII-mediated downregulation of migration and invasion in vitro and T beta RIII-mediated inhibition of breast cancer progression in vivo. Functionally, the cytoplasmic domain of T beta RIII is required to attenuate TGF-beta signaling, whereas T beta RIII-mediated attenuation of TGF-beta signaling is required for T beta RIII-mediated inhibition of migration and invasion. Mechanistically, both T beta RIII-mediated inhibition of TGF-beta signaling and T beta RIII-mediated inhibition of invasion occur through the interaction of the cytoplasmic domain of T beta RIII with the scaffolding protein GAIP-interacting protein C-terminus (GIPC). Taken together, these studies support a functional role for the T beta RIII cytoplasmic domain interacting with GIPC to suppress breast cancer progression.