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

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Abstract

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.

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Author and article information

Journal

Journal ID (nlm-journal-id): 8711562

Journal ID (pubmed-jr-id): 6325

Journal ID (nlm-ta): Oncogene

Title: Oncogene

ISSN (Print): 0950-9232

ISSN (Electronic): 1476-5594

Publication date Nihms-submitted: 21 September 2009

Publication date (Electronic): 2 November 2009

Publication date (Print): 28 January 2010

Publication date PMC-release: 28 July 2010

Volume: 29

Issue: 4

Pages: 539-549

Affiliations

[1 ] Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA

[2 ] Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA

[3 ] Department of Biochemistry and Molecule Biology, Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA

Author notes

Correspondence: Dr. Guojun Bu, Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., CB 8208, St. Louis, MO 63110, USA, bu@ 123456wustl.edu , Pone: (314)286-2860

[*]

The authors have equal contribution to this paper

Article

Manuscript ID: nihpa146777

DOI: 10.1038/onc.2009.339

PMC ID: 2813429

PubMed ID: 19881541

SO-VID: b0ff265a-e3f7-4a91-9813-9111c68fb7bf

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