ABSTRACT MUC1, a mucin-like transmembrane glycoprotein, is highly overexpressed and aberrantly localized in several invasive carcinomas. MUC1 is proposed to play numerous roles in the transformed behaviour of cells in which it is expressed. A number of these roles are facilitated by the interaction of MUC1 with β-catenin, a protein that is central to both cellular adhesion as well as Wnt-responsive gene transcription. The aim of this study was to investigate MUC1 expression, localization, and interaction with β-catenin, as a means of providing insight into the behaviour of human oesophageal squamous cell carcinoma. This cancer-type is exceptionally aggressive and is a major cause of cancer-related morbidity and mortality in South Africa. MUC1 is expressed and aberrantly localized in oesophageal squamous cell carcinoma cell lines, as demonstrated by RT-PCR, western blotting and indirect immunofluorescence. Moreover, evidence from coimmunoprecipitation assays shows that the MUC1 cytoplasmic tail and β-catenin form a complex both at the cell membrane and importantly, within the nucleus of these cell lines. This is the first demonstration of such a complex in the nucleus of a carcinoma derived from stratified, as opposed to simple, epithelia. Data presented here further indicates that activation of the epidermal growth factor receptor results in modulation of the association between MUC1 and β-catenin at the cell membrane. MUC1 membrane-localization, and interaction with β-catenin, may modulate cellular adhesion through steric interference of cell surface adhesion molecules as well as through sequestration of β-catenin away from adherens junctions. On the other hand, MUC1 association with β-catenin may enhance β- catenin signalling either through the stabilization of β-catenin, or as an essential functional component of the β-catenin/LEF/TCF transcription factor complex. Furthermore, results presented in this study identify oesophageal squamous cell carcinoma as a prime candidate for MUC1-specific immunotherapy. This finding is of substantial importance considering the ineffectual nature of existing therapies used in the treatment of oesophageal carcinoma.