A β-catenin survival signal is required for normal lobular development in the mammary gland

The Wnt (wingless) family of secreted glycoproteins initiates a signalling pathway implicated in the regulation of both normal mouse mammary gland development and tumorigenesis. Multiple Wnt signals ultimately converge on the multifunctional protein β-catenin to activate the transcription of target genes. Although β-catenin plays a crucial role in canonical Wnt signalling, it also functions in epithelial cell-cell adhesion at the adherens junctions. This study was designed to isolate β-catenin's signalling function from its role in adherence during mouse mammary gland development. A transgenic dominant-negative β-catenin chimera (β-eng), which retains normal protein-binding properties of wild-type β-catenin but lacks its C-terminal signalling domain, was expressed preferentially in the mammary gland. Thus, β-eng inhibits the signalling capacity of endogenous β-catenin, while preserving normal cell-cell adhesion properties. Analysis of the mammary gland in transgenic mice revealed a severe inhibition of lobuloalveolar development and a failure of the mice to nurse their young. Expression of β-eng resulted in an induction of apoptosis both in transgenic mice and in retrovirally transduced HC11 cells. Thus, endogenous β-catenin expression appears to be required to provide a survival signal in mammary epithelial cells, which can be suppressed by transgenic expression of β-eng. Comparison of the timing of transgene expression with the transgenic phenotype suggested a model in which β-catenin's survival signal is required in lobular progenitors that later differentiate into lobuloalveolar clusters. This study illustrates the importance of β-catenin signalling in mammary lobuloalveolar development.