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

Salvatore Pece, Michela Serresi, Elisa Santolini, Maria Capra, Esther Hulleman, Viviana Galimberti, Stefano Zurrida, Patrick Maissonneuve, Giuseppe Viale, Pier Paolo di Fiore

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.
Originele taal-2Engels
Pagina's (van-tot)215-221
TijdschriftThe Journal of Cell Biology
Volume167
Nummer van het tijdschrift2
DOI's
StatusGepubliceerd - 25 okt. 2004
Extern gepubliceerdJa

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