Fodrin, E-cadherin, and beta-catenin immunolocalization was studied in 54 cases of infiltrating ductal carcinoma of the breast and compared with an in vitro model in order to study the dynamic relationship between these components of an adhesion complex. In low-grade tumours, the staining patterns were similar for both fodrin and E-cadherin, with localization of these proteins to the cell membranes. beta-Catenin showed reduced membrane staining compared with non-neoplastic epithelium. High-grade tumours displayed strong membranous as well as cytoplasmic immunolocalization of fodrin, while E-cadherin staining was fragmented or lost from the membranes, with only occasional weak intracellular staining. beta-Catenin showed fragmented membrane staining and cytoplasmic accumulation. In addition, nuclear staining of beta-catenin was occasionally observed. In a v-src-transformed MDCK cell line, following 15min of src activation, beta-catenin began to detach from the cell membrane and localize to the cytoplasm, while fodrin and E-cadherin remained unchanged. After 30-45min of src activation, the cells lost their cuboidal shape and began to lose cell-to-cell contact. Fodrin staining remained mostly membranous while that of E-cadherin and beta-catenin was fragmented and spiky. After 60min of src activation, fodrin localized completely in the cell cytoplasm, while E-cadherin and beta-catenin were partly cytoplasmic with fragmented and spiky membranous staining. Occasionally, beta-catenin was seen in the nucleus. Both in vivo and in vitro findings clearly demonstrated a disruption of the E-cadherin/beta-catenin/fodrin/cytoskeleton linkage concomitant with the loss of cell-to-cell adhesion and change in cell shape, from epithelioid to a fibroblastoid phenotype. Membranous localization of E-cadherin showed a positive correlation with oestrogen and progesterone expression, whereas loss of membranous E-cadherin and cytoplasmic accumulation of fodrin was more often observed in high-grade carcinomas and showed a positive correlation with p53 expression.