Notch1-induced brain tumor models the sonic hedgehog subgroup of human medulloblastoma

Sivaraman Natarajan, Yaochen Li, Emily E Miller, David J Shih, Michael D Taylor, Timothy M Stearns, Roderick T Bronson, Susan L Ackerman, Jeong K Yoon, Kyuson Yun

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5381-90
Number of pages10
JournalCancer research
Volume73
Issue number17
DOIs
StatePublished - Sep 1 2013

Keywords

  • Animals
  • Apoptosis
  • Biomarkers, Tumor
  • Blotting, Western
  • Brain Neoplasms
  • Cell Differentiation
  • Cell Proliferation
  • Cerebellar Neoplasms
  • Fluorescent Antibody Technique
  • Gene Expression Profiling
  • Hedgehog Proteins
  • Humans
  • Immunoenzyme Techniques
  • Medulloblastoma
  • Mice
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger
  • Real-Time Polymerase Chain Reaction
  • Receptor, Notch1
  • Reverse Transcriptase Polymerase Chain Reaction
  • Journal Article
  • Research Support, N.I.H., Extramural

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