In several cancers, including breast cancer, loss of E-cadherin expression is correlated with a loss of the epithelial phenotype and with a gain of invasiveness. Cells that have lost E-cadherin expression are either poorly invasive with a rounded phenotype, or highly invasive, with a mesenchymal phenotype. Most cells lacking E-cadherin still retain weak calcium-dependent adhesion, indicating the presence of another cadherin family member. We have now examined the expression of the mesenchymal cadherin, cadherin-11, in breast cancer cell lines. Cadherin-11 mRNA and protein, as well as a variant form, are expressed in the most invasive cell lines but not in any of the noninvasive cell lines. Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin. Immunocytochemistry shows that cadherin-11 is localized to the cell membrane at sites of cell-cell contact as well as at lamellipodia-like projections, which do not interact with other cells. These results suggest that cadherin-11 expression may be well correlated with the invasive phenotype in cancer cells and may serve as a molecular marker for the more aggressive, invasive subset of tumors. Cadherin-11 may mediate the interaction between malignant tumor cells and other cell types that normally express cadherin-11, such as stromal cells or osteoblasts or perhaps even with the surrounding extracellular matrix, thus facilitating tumor cell invasion and metastasis.