Veronica D'Uva

Numb acts as tumor suppressor in the human mammary gland by inhibiting Notch signaling and stabilizing p53. Loss of Numb is detected in ~30% of breast cancers and correlates with an adverse prognosis. The best characterized mechanism for Numb loss is degradation of the protein by the ubiquitin-proteasome machinery. At the molecular level, Numb binds to and inhibits the activity of Mdm2, the E3 ligase that mediates p53 ubiquitination and successive degradation. A short Numb region encompassing the alternatively spliced exon 3 is necessary and sufficient to inhibit Mdm2 and stabilize p53. The aim of this project is to define the function of Numb isoforms in p53 regulation and their clinical relevance in breast cancer. We demonstrated the exclusive role of Numb isoforms containing the exon 3-coded insert in regulating the p53 circuitry. Alterations in the Numb splicing pattern have clinical implications in breast cancer. Indeed, p53 WT tumors displaying reduced levels of exon 3-containing Numb isoforms showed increased chemoresistance and risk of relapse. A similar effect was also observed in tumors displaying low levels of Numb mRNA, revealing that transcriptional deregulation represents an additional mechanism responsible for loss of Numb expression. Our data demonstrate that specific Numb isoforms and global Numb mRNA levels correlate with chemoresistance and tumor progression in p53-competent breast cancers.