Notch1 and notch2 have opposite effects on embryonal brain tumor growth.
The role of Notch signaling in tumorigenesis can vary; Notch1 acts as an oncogene in some neoplasms, and a tumor suppressor in others. Here, we show that different Notch receptors can have opposite effects in a single tumor type. Expression of truncated, constitutively active Notch1 or Notch2 in embryonal brain tumor cell lines caused antagonistic effects on tumor growth. Cell proliferation, soft agar colony formation, and xenograft growth were all promoted by Notch2 and inhibited by Notch1. We also found that Notch2 receptor transcripts are highly expressed in progenitor cell-derived brain tumors such as medulloblastomas, whereas Notch1 is scarce or undetectable. This parallels normal cerebellar development, during which Notch2 is predominantly expressed in proliferating progenitors and Notch1 in postmitotic differentiating cells. Given the oncogenic effects of Notch2, we analyzed its gene dosage in 40 embryonal brain tumors, detecting an increased copy number in 15% of cases. Notch2 gene amplification was confirmed by fluorescence in situ hybridization in one case with extremely high Notch2 mRNA levels. In addition, expression of the Notch pathway target gene Hes1 in medulloblastomas was associated with significantly shorter patient survival (P = 0.01). Finally, pharmacological inhibition of Notch signaling suppresses growth of medulloblastoma cells. Our data indicate that Notch1 and Notch2 can have opposite effects on the growth of a single tumor type, and show that Notch2 can be overexpressed after gene amplification in human tumors.
Fan
Xing
X
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Mikolaenko
Irina
I
Elhassan
Ihab
I
Ni
Xingzhi
X
Wang
Yunyue
Y
Ball
Douglas
D
Brat
Daniel J
DJ
Perry
Arie
A
Eberhart
Charles G
CG
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001932:Brain Neoplasms / Q000473:pathology*; D002455:Cell Division; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000473:pathology*; D018628:Gene Dosage; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008527:Medulloblastoma / Q000473:pathology; D051379:Mice; D018242:Neuroectodermal Tumors, Primitive / Q000473:pathology*; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; C078493:HES1 protein, human