TY - JOUR
T1 - The Numb/p53 circuitry couples replicative self-renewal and tumor suppression in mammary epithelial cells
AU - Tosoni, Daniela
AU - Zecchini, Silvia
AU - Coazzoli, Marco
AU - Colaluca, Ivan
AU - Mazzarol, Giovanni
AU - Rubio, Alicia
AU - Caccia, Michele
AU - Villa, Emanuele
AU - Zilian, Olav
AU - Di Fiore, Pier Paolo
AU - Pece, Salvatore
PY - 2015/11/23
Y1 - 2015/11/23
N2 - The cell fate determinant Numb orchestrates tissue morphogenesis and patterning in developmental systems. In the human mammary gland, Numb is a tumor suppressor and regulates p53 levels. However, whether this function is linked to its role in fate determination remains unclear. Here, by exploiting an ex vivo system, we show that at mitosis of purified mammary stem cells (SCs), Numb ensures the asymmetric outcome of self-renewing divisions by partitioning into the progeny that retains the SC identity, where it sustains high p53 activity. Numb also controls progenitor maturation. At this level, Numb loss associates with the epithelial-to-mesenchymal transition and results in differentiation defects and reacquisition of stemness features. The mammary gland of Numb-knockout mice displays an expansion of the SC compartment, associated with morphological alterations and tumorigenicity in orthotopic transplants. This is because of low p53 levels and can be inhibited by restoration of Numb levels or p53 activity, which results in successful SC-targeted treatment.
AB - The cell fate determinant Numb orchestrates tissue morphogenesis and patterning in developmental systems. In the human mammary gland, Numb is a tumor suppressor and regulates p53 levels. However, whether this function is linked to its role in fate determination remains unclear. Here, by exploiting an ex vivo system, we show that at mitosis of purified mammary stem cells (SCs), Numb ensures the asymmetric outcome of self-renewing divisions by partitioning into the progeny that retains the SC identity, where it sustains high p53 activity. Numb also controls progenitor maturation. At this level, Numb loss associates with the epithelial-to-mesenchymal transition and results in differentiation defects and reacquisition of stemness features. The mammary gland of Numb-knockout mice displays an expansion of the SC compartment, associated with morphological alterations and tumorigenicity in orthotopic transplants. This is because of low p53 levels and can be inhibited by restoration of Numb levels or p53 activity, which results in successful SC-targeted treatment.
UR - http://www.scopus.com/inward/record.url?scp=84970946060&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84970946060&partnerID=8YFLogxK
U2 - 10.1083/jcb.201505037
DO - 10.1083/jcb.201505037
M3 - Article
AN - SCOPUS:84970946060
VL - 211
SP - 845
EP - 862
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 4
ER -