title: The Numb/p53 circuitry couples replicative self-renewal and tumor suppression in mammary epithelial cells.
abstract: 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.
authors.affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Tosoni
authors.affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zecchini
authors.affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Coazzoli
authors.affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Colaluca
authors.affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mazzarol
authors.affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors.forename: Alicia
authors.initials: A
authors.lastname: Rubio
authors.affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Caccia
authors.affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Villa
authors.affiliation: Helvea SA, 1207 Geneva, Switzerland.
authors.forename: Olav
authors.initials: O
authors.lastname: Zilian
authors.affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20142 Milan, Italy Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy pierpaolo.difiore@ifom.eu salvatore.pece@ieo.eu.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.affiliation: Istituto Europeo di Oncologia, 20141 Milan, Italy Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy pierpaolo.difiore@ifom.eu salvatore.pece@ieo.eu.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pece
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D000066673:Cell Self Renewal; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D004847:Epithelial Cells / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008938:Mitosis; D009024:Morphogenesis; D014411:Neoplastic Stem Cells / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D021381:Protein Transport; D018874:Spheroids, Cellular / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; D016159:Tumor Suppressor Protein p53