TRANSFORMATION BY WNT FAMILY PROTEINS CORRELATES WITH REGULATION OF BETA-CATENIN

Several members of the Wnt family of secreted factors are strongly imp licated as regulators of mammary cell growth and differentiation. To i nvestigate Wnt signaling in mammary cells, we have assessed the abilit ies of 10 different Wnt genes to cause transformation of C57MG mammary epithelial cells and in parallel studied their effects on beta-cateni n, a component of the Wnt-1 signaling pathway. Autocrine transforming potential was tested by expression of Wnt proteins in C57MG cells, and paracrine effects were evaluated by coculture of C57MG cells with fib roblasts secreting different Wnt proteins. Western blotting confirmed the expression of each Wnt protein in the relevant cell lines. Activit ies of the 10 Wnts tested were divisible into three groups. Wnt-1, Wnt -2, Wnt-3, and Wnt-3a induced strong transformation and an elongated r efractile cell morphology. Wnt-6 and Wnt-7a produced weak morphologica l changes. Wnt-4, Wnt-5a, Wnt-5b, and Wnt-7b had no effect at all on C 57MG morphology. Analysis of beta-catenin levels showed that the trans forming Wnts induced accumulation of cytosolic beta-catenin, whereas n ontransforming Wnts did not. These results demonstrate that several Wn t family members are capable of elevating beta-catenin levels and sugg est that their signaling pathways share intracellular signaling compon ents. The correlation between increased cytosolic beta-catenin levels and C57MG transformation supports a role for beta-catenin in transform ation of these cells. These data also imply the existence of receptors that respond to certain Wnt proteins but not to others.