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Published online 18 October 2004. doi:10.1083/jcb.200406140
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 2, 215-221
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 Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis

Salvatore Pece1,2, Michela Serresi1, Elisa Santolini1, Maria Capra1,3, Esther Hulleman1, Viviana Galimberti1, Stefano Zurrida1, Patrick Maisonneuve1, Giuseppe Viale1,2, and Pier Paolo Di Fiore1,2,3

1 Istituto Europeo di Oncologia, 20141 Milan, Italy
2 Dipartimento di Medicina, Chirurgia ed Odontoiatria, Università degli Studi di Milano, 20122 Milan, Italy
3 Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, 20139 Milan, Italy

Correspondence to P.P. Di Fiore: difiore{at}ifom-firc.it


Abstract
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 ~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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