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Alterations in ß-Catenin Phosphorylation and Plakoglobin Expression in Human Breast Cancer Cells

Departments of Cell Biology [C. L. S., S. W. B., E. P. G.] and Medicine [E. P. G.], Georgetown University School of Medicine, and the Lombardi Cancer Research Center, Washington, D.C. 20007; Max-Planck-Institut für Immunobiologie, Freiburg, D:7800 Germany [R. K.]; and Department of Cell Biology, New York University, New York 10016 [P. C.]

Because the cell adhesion molecule epithelial cadherin (E-cadherin) is absent in many invasive carcinomas, we transfected the E-cadherin gene into E-cadherin-negative, invasive breast cancer cell lines BT549 and HS578t to investigate the role of E-cadherin in invasive behavior. Although the transfected E-cadherin could mediate calcium-dependent aggregation to E-cadherin-transfected L-cells, morphology and invasiveness of the breast cancer cells were not altered. We investigated the strength of the linkage of the transfected E-cadherin to the actin cytoskeleton by examining the Triton X-100 solubility of the transfected E-cadherin. In BT549 and HS578t cells, a large proportion of the transfected E-cadherin was Triton soluble, whereas in E-cadherin-positive MCF-7 cells, Triton-insoluble E-cadherin was apparent at cell-cell borders. Interaction of E-cadherin with the actin cytoskeleton is thought to be mediated by the E-cadherin-binding proteins -catenin, ß-catenin, and plakoglobin. We found normal levels of -catenin and ß-catenin in BT549 and HS578t cells; however, low levels of plakoglobin were expressed in these cells compared to those found in weakly invasive MCF-7 cells. Furthermore, levels of tyrosine phosphorylation of ß-catenin were elevated in E-cadherin-transfected BT549 and HS578t cells compared to MCF-7 cells. We conclude that other factors such as the expression and appropriate posttranslational modification of cadherin-associated proteins must be in place for E-cadherin to be fully functional, i.e., to alter invasiveness. During cancer progression, loss of E-cadherin expression itself or multiple other mechanisms that lead to loss of cell-cell adhesion (mutation, loss of catenin expression, alterations in phosphorylation) may contribute to a more metastatic phenotype.

¹ To whom requests for reprints should be addressed, at Department of Cell Biology, Georgetown University School of Medicine, 3900 Reservoir Road N.W., Washington, DC 20007.

Received 12/22/93. Accepted 4/25/94.

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