Alterations of the Notch pathway in lung cancer

Notch signaling regulates cell specification and homeostasis of stem cell compartments, and it is counteracted by the cell fate determinant Numb. Both Numb and Notch have been implicated in human tumors. Here, we show that Notch signaling is altered in approximately one third of non-small-cell lung...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-12, Vol.106 (52), p.22293-22298
Main Authors: Westhoff, Britta, Colaluca, Ivan N, D'Ario, Giovanni, Donzelli, Maddalena, Tosoni, Daniela, Volorio, Sara, Pelosi, Giuseppe, Spaggiari, Lorenzo, Mazzarol, Giovanni, Viale, Giuseppe, Pece, Salvatore, Di Fiore, Pier Paolo
Format: Article
Language:English
Subjects:
Aged
Base Sequence
Basic Helix-Loop-Helix Transcription Factors - genetics
Basic Helix-Loop-Helix Transcription Factors - metabolism
Biological Sciences
Breast cancer
Cancer
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - metabolism
Carcinoma, Non-Small-Cell Lung - pathology
Clinical outcomes
DNA Mutational Analysis
DNA, Neoplasm - genetics
Female
Gene Expression
Genetic mutation
HeLa cells
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Lung cancer
Lung neoplasms
Lung Neoplasms - genetics
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Lungs
Male
Membrane Proteins - genetics
Membrane Proteins - metabolism
Messenger RNA
Middle Aged
Mutation
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Non small cell lung carcinoma
Receptor, Notch1 - genetics
Receptor, Notch1 - metabolism
Receptors, Notch - genetics
Receptors, Notch - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA, Neoplasm - genetics
RNA, Neoplasm - metabolism
Signal Transduction
Stem cells
Transcription Factor HES-1
Tumor Cells, Cultured
Tumors
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Description
Summary:Notch signaling regulates cell specification and homeostasis of stem cell compartments, and it is counteracted by the cell fate determinant Numb. Both Numb and Notch have been implicated in human tumors. Here, we show that Notch signaling is altered in approximately one third of non-small-cell lung carcinomas (NSCLCs), which are the leading cause of cancer-related deaths: in [almost equal to]30% of NSCLCs, loss of Numb expression leads to increased Notch activity, while in a smaller fraction of cases (around 10%), gain-of-function mutations of the NOTCH-1 gene are present. Activation of Notch correlates with poor clinical outcomes in NSCLC patients without TP53 mutations. Finally, primary epithelial cell cultures, derived from NSCLC harboring constitutive activation of the Notch pathway, are selectively killed by inhibitors of Notch (γ-secretase inhibitors), showing that the proliferative advantage of these tumors is dependent upon Notch signaling. Our results show that the deregulation of the Notch pathway is a relatively frequent event in NSCLCs and suggest that it might represent a possible target for molecular therapies in these tumors.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0907781106