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Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):E388-97. doi: 10.1073/pnas.1120421109. Epub 2012 Jan 20.

Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity.

Author information

1
Institute of Biomedicine and Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.

Abstract

Although loss of epithelial integrity is a hallmark of advanced cancer, it remains poorly understood whether genetic alterations corrupting this integrity causally facilitate tumorigenesis. We show that conditional deletion of tumor suppressor gene Lkb1 (Par-4) in the mammary gland compromises epithelial integrity manifested by mislocalization of cell polarity markers, lateralization of tight junctions, deterioration of desmosomes and basement membrane (BM), and hyperbranching of the mammary ductal tree. We identify the desmosomal BM remodelling serine protease Hepsin as a key factor mediating Lkb1 loss-induced structural alterations in mammary epithelium and BM fragmentation. Although loss of Lkb1 alone does not promote mammary tumorigenesis, combination of Lkb1 deficiency with oncogenic c-Myc leads to dramatic acceleration in tumor formation. The results coupling Lkb1 loss-mediated epithelial integrity defects to mislocalization of serine protease Hepsin and to oncogenic synergy with c-Myc imply that Lkb1 loss facilitates oncogenic proliferation by releasing epithelial cells from structural BM boundaries.

PMID:
22308451
PMCID:
PMC3289385
DOI:
10.1073/pnas.1120421109
[Indexed for MEDLINE]
Free PMC Article

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