title: Activated Notch1 induces lung adenomas in mice and cooperates with Myc in the generation of lung adenocarcinoma.
abstract: Notch1 encodes the canonical member of the mammalian Notch receptor family. Activating lesions frequently affect Notch1 in T-cell acute lymphoblastic leukemia (T-ALL) and, recently, have been found in non-small-cell lung cancer (NSCLC) as well. We explored the oncogenic potential of activated Notch1 in the lung by developing a transgenic mouse model in which activated Notch1 was overexpressed in the alveolar epithelium. The initial response to activated Notch1 was proliferation and the accumulation of alveolar hyperplasia, which was then promptly cleared by apoptosis. After an extended latency period, however, pulmonary adenomas appeared in the transgenic mice but failed to progress to become carcinomas. Interestingly, Myc and MycL1 were expressed in the adenomas, suggesting that selection for enhanced Myc activity may facilitate tumorigenesis. Using mice engineered to coexpress activated Notch1 and Myc, we found that supplementing Myc expression resulted in increased frequency of Notch1 intracellular domain (N1ICD)-induced adenoma formation and enabled progression to adenocarcinoma and metastases. Cooperation stemmed from synergistic activation of tumor cell cycling, a process that apparently countered any impedance to tumorigenesis posed by Myc and/or activated Notch1-induced apoptosis. Significantly, cooperation was independent of RAS activation. Taken together, the data suggest that activated Notch1 substitutes for RAS activation synergistically with Myc in the development of NSCLC. These tumor models should be valuable for exploring the role of activated Notch1 in the genesis of NSCLC and for testing therapies targeting either activated Notch1 or its downstream effectors.
authors.affiliation: G.W. Hooper Research Foundation, University of California, San Francisco, San Francisco, California 94143-0552, USA. Thaddeus.Allen@ucsf.edu
authors.forename: Thaddeus D
authors.initials: TD
authors.lastname: Allen
authors.forename: Elena M
authors.initials: EM
authors.lastname: Rodriguez
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Jones
authors.forename: J Michael
authors.initials: JM
authors.lastname: Bishop
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016259:Genes, myc; D006801:Humans; D006965:Hyperplasia; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics*; D019076:Transgenes; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism
chemical_list: C489427:MYC protein, human; C489428:Myc protein, mouse; C587451:Mycl1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D025803:Tumor Suppressor Protein p14ARF; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras)