Many proteins enhance cancer progression towards life-threatening metastases. These include linking proteins called integrins which mediate cell adhesion to the extracellular matrix (ECM), consequently altering both function and phenotype. Specific neoexpression of the β6 integrin subunit correlates with the epithelial-to-mesenchymal transition, metastasis and with poor overall patient survival. Whilst b6 is implicated in these processes, exactly how it affects signaling and/or proteolytic pathways in metastasis remains unclear. A membrane-enriched peptide IPG-IEF shotgun proteomics study was undertaken comparing subclones of the SW480 CRC cell line transfected with a vector inducing unregulated β6 integrin overexpression against the ‘empty’ mock vector control cell line. β6 overexpression induced a significant change in 708 proteins found localised across most intracellular locations, some involving cellular processes and pathways underpinning cancer progression. β6 expression increased cell proliferation 4-fold, while decreasing cell adhesion to many integrin-ECM substrates. β6 expression also enhanced cell invasion and promoted the expression/repression of many established cancer-related pathways.