Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis.
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.
Pece
Salvatore
S
Istituto Europeo di Oncologia, 20141 Milan, Italy.
Serresi
Michela
M
Santolini
Elisa
E
Capra
Maria
M
Hulleman
Esther
E
Galimberti
Viviana
V
Zurrida
Stefano
S
Maisonneuve
Patrick
P
Viale
Giuseppe
G
Di Fiore
Pier Paolo
PP
D001943:Breast Neoplasms / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D029721:Drosophila Proteins; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007605:Juvenile Hormones / Q000378:metabolism / Q000502:physiology*; D019656:Loss of Heterozygosity; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D008856:Microscopy, Fluorescence; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051880:Receptors, Notch; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism
D029721:Drosophila Proteins; D007605:Juvenile Hormones; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D025801:Ubiquitin; C060606:numb protein, Drosophila; D049452:Green Fluorescent Proteins; D008156:Luciferases; D046988:Proteasome Endopeptidase Complex