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Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis.

Authors: Pece, S  Serresi, M  Santolini, E  Capra, M  Hulleman, E  Galimberti, V  Zurrida, S  Maisonneuve, P  Viale, G  Di Fiore, PP 
Citation: Pece S, etal., J Cell Biol 2004 Oct 25;167(2):215-21. Epub 2004 Oct 18.
Pubmed: (View Article at PubMed) PMID:15492044
DOI: Full-text: DOI:10.1083/jcb.200406140

The biological antagonism between Notch and Numb controls the proliferative/differentiative balance in development and homeostasis. Although altered Notch signaling has been linked to human diseases, including cancer, evidence for a substantial involvement of Notch in human tumors has remained elusive. Here, we show that Numb-mediated control on Notch signaling is lost in approximately 50% of human mammary carcinomas, due to specific Numb ubiquitination and proteasomal degradation. Mechanistically, Numb operates as an oncosuppressor, as its ectopic expression in Numb-negative, but not in Numb-positive, tumor cells inhibits proliferation. Increased Notch signaling is observed in Numb-negative tumors, but reverts to basal levels after enforced expression of Numb. Conversely, Numb silencing increases Notch signaling in normal breast cells and in Numb-positive breast tumors. Finally, growth suppression of Numb-negative, but not Numb-positive, breast tumors can be achieved by pharmacological inhibition of Notch. Thus, the Numb/Notch biological antagonism is relevant to the homeostasis of the normal mammary parenchyma and its subversion contributes to human mammary carcinogenesis.


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CRRD Object Information
CRRD ID: 1334451
Created: 2005-02-08
Species: All species
Last Modified: 2005-02-08
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.