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Department of Cell Biology, University of Virginia, Charlottesville, VA 22908

Address correspondence to Barry M. Gumbiner, Dept. of Cell Biology, School of Medicine, University of Virginia, PO Box 800732, Charlottesville, VA 22903. Tel.: (434) 243-9290. Fax: (434) 924-2794. E-mail: gumbiner{at}virginia.edu

Loss of E-cadherin expression or function in tumors leads to a more invasive phenotype. In this study, we investigated whether the invasion suppressor activity of E-cadherin is mediated directly by tighter physical cell adhesion, indirectly by sequestering ß-catenin and thus antagonizing ß-catenin/T cell factor (TCF) signaling, or by other signaling pathways. To distinguish mechanisms, we expressed wild-type E-cadherin and various E-cadherin mutants in invasive E-cadherin–negative human breast (MDA-MB-231) and prostate (TSU-Pr1) epithelial carcinoma cell lines using a tetracycline-inducible system. Our data confirm that E-cadherin inhibits human mammary and prostate tumor cell invasion. We find that adhesion is neither necessary nor sufficient for suppressing cancer invasion. Rather, the invasion suppressor signal is mediated through the ß-catenin–binding domain of the E-cadherin cytoplasmic tail but not through the p120^ctn-binding domain. ß-catenin depletion also results in invasion suppression. However, alteration in the ß-catenin/TCF transcriptional regulation of target genes is not required for the invasion suppressor activity of E-cadherin, suggesting the involvement of other ß-catenin–binding proteins.

Key Words: E-cadherin; b-catenin; invasion; adhesion; signaling

^* Abbreviations used in this paper: LEF, leukocyte enhancer factor; NS, nonspecific; rtTA, reverse tetracycline-responsive transcriptional activator; siRNA, small interfering RNA; TCF, T cell factor.

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