title: Notch1-induced brain tumor models the sonic hedgehog subgroup of human medulloblastoma.
abstract: While activation of the Notch pathway is observed in many human cancers, it is unknown whether elevated Notch1 expression is sufficient to initiate tumorigenesis in most tissues. To test the oncogenic potential of Notch1 in solid tumors, we expressed an activated form of Notch1 (N1ICD) in the developing mouse brain. N1ICD;hGFAP-cre mice were viable but developed severe ataxia and seizures, and died by weaning age. Analysis of transgenic embryo brains revealed that N1ICD expression induced p53-dependent apoptosis. When apoptosis was blocked by genetic deletion of p53, 30% to 40% of N1ICD;GFAP-cre;p53(+/-) and N1ICD;GFAP-cre;p53(-/-) mice developed spontaneous medulloblastomas. Interestingly, N1ICD-induced medulloblastomas most closely resembled the sonic hedgehog subgroup of human medulloblastoma at the molecular level. Surprisingly, N1ICD-induced tumors do not maintain high levels of the Notch pathway gene expression, except for Notch2, showing that initiating oncogenic events may not be decipherable by analyzing growing tumors in some cases. In summary, this study shows that Notch1 has an oncogenic potential in the brain when combined with other oncogenic hits, such as p53 loss, and provides a novel mouse model of medulloblastoma. Cancer Res; 73(17); 5381-90. ©2013 AACR.
authors.affiliation: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, USA.
authors.forename: Sivaraman
authors.initials: S
authors.lastname: Natarajan
authors.forename: Yaochen
authors.initials: Y
authors.lastname: Li
authors.forename: Emily E
authors.initials: EE
authors.lastname: Miller
authors.forename: David J
authors.initials: DJ
authors.lastname: Shih
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Stearns
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ackerman
authors.forename: Jeong K
authors.initials: JK
authors.lastname: Yoon
authors.forename: Kyuson
authors.initials: K
authors.lastname: Yun
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000145:classification / Q000235:genetics / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008527:Medulloblastoma / Q000145:classification / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D053823:Hedgehog Proteins; C497762:Notch1 protein, mouse; D012333:RNA, Messenger; D051881:Receptor, Notch1; C465570:Shh protein, mouse