TY - JOUR
T1 - Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis
AU - Pece, Salvatore
AU - Serresi, Michela
AU - Santolini, Elisa
AU - Capra, Maria
AU - Hulleman, Esther
AU - Galimberti, Viviana
AU - Zurrida, Stefano
AU - Maissonneuve, Patrick
AU - Viale, Giuseppe
AU - di Fiore, Pier Paolo
PY - 2004/10/25
Y1 - 2004/10/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=7244250027&partnerID=8YFLogxK
U2 - 10.1083/jcb.200406140
DO - 10.1083/jcb.200406140
M3 - Article
SN - 0021-9525
VL - 167
SP - 215
EP - 221
JO - The Journal of Cell Biology
JF - The Journal of Cell Biology
IS - 2
ER -