Mammary specific Lunatic Fringe deletion results in tumor development with Met amplification, and cooperates with Trp53 mutation in tumorigenesis.

摘要

Mammary deletion of Lunatic Fringe (Lfng), an enzyme that regulates Notch receptor-ligand interactions, results in Basal-like tumor formation. Notch regulates mammary cell differentiation, and aberrant activity results in tumorigenesis. Lfng deficient mice develop Basal-like tumors with Met amplification. I studied Met expression in these tumors, and found it's expressed by a subset of tumor cells. Expression was associated with hypoxia, and found in epithelial-to-mesenchymal transition (EMT) regions, and near necrosis. Since Met is a transcriptional target of hypoxia-inducible factor 1, it's likely that hypoxia results in increased Met expression. Met also co-expressed with luminal cell marker Cytokeratin 8 and progenitor marker Aldehyde dehydrogenase I. Finally, I tested for cooperation between Lfng deficiency and Trp53R270H mutation in tumorigenesis. Double mutant mice showed decreased tumor-free survival suggesting a cooperative relationship. My work suggests that Met plays a role in luminal/progenitor-like cells and cooperation between Lfng deficiency and Trp53R270H results in reduced survival.