Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity.
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.
Institute of Biomedicine and Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
Johanna I
JI
Partanen
Topi A
TA
Tervonen
Mikko
M
Myllynen
Essi
E
Lind
Misa
M
Imai
Pekka
P
Katajisto
Gerrit J P
GJ
Dijkgraaf
Panu E
PE
Kovanen
Tomi P
TP
Mäkelä
Zena
Z
Werb
Juha
J
Klefström
D055372:AMP-Activated Protein Kinases; D000818:Animals; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D016259:Genes, myc; D008321:Mammary Glands, Animal / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*
D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases