WNT-5a-CKIalpha signaling promotes beta -catenin/E-cadherin complex formation and intercellular adhesion in human breast epithelial cells.

Wnt-5a is a non-transforming Wnt protein that is implicated in cell-polarity, adhesion and motility. We have previously shown that low expression of Wnt-5a is a predictor of shorter disease-free survival in human breast cancer. Here, we investigated whether ss-catenin/E-cadherin mediated cell-cell adhesion was affected by loss of Wnt-5a in breast carcinomas, thereby promoting a metastatic behavior of the tumor. We show that Wnt-5a stimulation of human breast epithelial cells leads to an increased Ca2+-dependent cell-cell adhesion. Furthermore, Wnt-5a/Casein Kinase Ia (CKIa)-specific Ser45-phosphorylation of ss-catenin is associated with an increased complex formation of ss-catenin/E-cadherin. Mutation of Ser45 decreases the ss-catenin/E-cadherin association. Also, the inhibitory effect of Wnt-5a on breast epithelial cell invasion is reduced upon mutation of ss-catenin-Ser45. The Wnt-5a-CKIa induced Ser45-phosphorylation does not lead to degradation of ss-catenin. Finally we show that human breast cancers lacking Wnt-5a protein have a significantly lower level of membrane-associated ss-catenin. Downregulation of Wnt-5a expression and subsequent reduction of membrane-associated ss-catenin in invasive breast cancer, can therefore contribute to a decreased cell-cell adhesion and increased motility resulting in a higher probability for metastatic disease