The movement of cells and the formation of tissues is dependent on the individual cell’s ability to attach to its surroundings. The attachment of cells to the surrounding extracellular matrix is principally mediated by integrin adhesion receptors. Integrins mediate bidirectional signalling across the plasma membrane, and by binding to components in the extracellular matrix, transform cues from their surroundings to changes in cell behaviour, such as dynamic restructuring of the cytoskeleton. The endosomal network is responsible for transporting molecules to their correct cellular locations. As cells migrate, integrins undergo continuous cycles of internalisation and endosomal recycling back to the cell surface to facilitate the dynamic assembly and disassembly of adhesions that enables sustained cell motility.

Cancer cells regulate endosomal receptor traffic to promote their malignancy. This includes promotion of integrin trafficking to facilitate cancer cell migration and invasion, and the regulation of growth factor receptor trafficking to promote oncogenic signalling. However, large gaps remain in our understanding of the mechanistic details behind these processes.

This thesis presents new insights into the regulation of integrin and human epidermal growth factor receptor HER2 traffic in breast cancer. In the first project, we aimed to determine the impact of the endosomal sorting receptor SORLA on the trafficking and oncogenic signalling of HER2, and found that SORLA directs endocytosed HER2 back to the cell surface to drive growth and survival signalling. In the second project, we investigated how Swiprosin-1 and Rab21 co-facilitate integrin endocytosis, and revealed that they direct integrins through the clathrin- and dynamin-independent CLIC/GEEC endocytic pathway, thus promoting integrin-mediated cell migration and invasion. In the third project, we studied the role of the actin-binding protein EPLIN and its isoforms in the context of integrin trafficking, and discovered that EPLINα localises to endosomes carrying integrin cargo, where it facilitates integrin recycling back to the cell surface to promote cell migration. Taken together, the results presented here increase our understanding of how breast cancer cells control receptor trafficking to promote their growth and motility, highlighting the significant impact that receptor trafficking has on cancer cell malignancy.