1. ¹Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA
2. ²Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA
3. ³Department of Biochemistry and Molecule Biology, Drug Discovery Division, Southern Research Institute, Birmingham, AL, USA

Correspondence: Dr G Bu, Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Ave., St Louis, MO 63110, USA. E-mail: bu@wustl.edu

⁴These authors contributed equally to this work.

Received 25 January 2009; Revised 10 September 2009; Accepted 17 September 2009; Published online 2 November 2009.

Abstract

Although Wnt signaling activation is frequently observed in human breast cancer, mutations in genes encoding intracellular components of the Wnt signaling pathway are rare. We found that the expression of Wnt signaling co-receptor, LRP6, is upregulated in a subset of human breast cancer tissues and cell lines. To examine whether the 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 -catenin from membrane to cytoplasmic/nuclear fractions. The 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 with wild-type littermate controls. Several matrix metalloproteinases are upregulated 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.