Wnt signaling activation and mammary gland hyperplasia in MMTV-LRP6 transgenic mice: implication for breast cancer tumorigenesis

Although Wnt signaling activation is frequently observed in human breast cancer, mutations in the genes encoding intracellular components of the Wnt signaling pathway are rare. We found that expression of Wnt signaling co-receptor LRP6 is up-regulated in a subset of human breast cancer tissues and cell lines. To examine whether overexpression of LRP6 in mammary epithelial cells is sufficient to activate Wnt signaling and promote cell proliferation, we generated transgenic mice overexpressing LRP6 in mammary epithelial cells driven by the mouse mammary tumor virus (MMTV) promoter. We found that mammary glands from MMTV-LRP6 mice exhibit significant Wnt activation evidenced by the translocation of β-catenin from membrane to cytoplasmic/nuclear fractions. Expression of several Wnt-target genes including Axin2, Cyclin D1 and c-Myc was also increased in MMTV-LRP6 mice. More importantly, mammary glands from virgin MMTV-LRP6 mice exhibit significant hyperplasia, a precursor to breast cancer, when compared to wild-type littermate controls. Several matrix metalloproteinases are up-regulated in MMTV-LRP6 mice that could contribute to the hyperplasia phenotype. Our results suggest that Wnt signaling activation at the cell surface receptor level can contribute to breast cancer tumorigenesis.