Loss of Negative Regulation by Numb over Notch is Relevant to Human Breast Carcinogenesis

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2004 Oct 20

PMID 15492044

Citations 223

Authors

Salvatore Pece

Michela Serresi

Elisa Santolini

Maria Capra

Esther Hulleman

Viviana Galimberti

Stefano Zurrida

Patrick Maisonneuve

Giuseppe Viale

Pier Paolo Di Fiore

Affiliations

Soon will be listed here.

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 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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