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 Maisonneuve, Giuseppe Viale, Pier Paolo Di Fiore

Research output: Contribution to journalArticlepeer-review

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 Numbpositive, 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.

Original languageEnglish
Pages (from-to)215-221
Number of pages7
JournalJournal of Cell Biology
Volume167
Issue number2
DOIs
Publication statusPublished - Oct 25 2004

ASJC Scopus subject areas

  • Cell Biology

Fingerprint

Dive into the research topics of 'Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis'. Together they form a unique fingerprint.

Cite this