title: Pre-clinical validation of a selective anti-cancer stem cell therapy for Numb-deficient human breast cancers.
abstract: The cell fate determinant Numb is frequently downregulated in human breast cancers (BCs), resulting in p53 inactivation and an aggressive disease course. In the mouse mammary gland, Numb/p53 downregulation leads to aberrant tissue morphogenesis, expansion of the stem cell compartment, and emergence of cancer stem cells (CSCs). Strikingly, CSC phenotypes in a Numb-knockout mouse model can be reverted by Numb/p53 restoration. Thus, targeting Numb/p53 dysfunction in Numb-deficient human BCs could represent a novel anti-CSC therapy. Here, using patient-derived xenografts, we show that expansion of the CSC pool, due to altered self-renewing divisions, is also a feature of Numb-deficient human BCs. In these cancers, using the inhibitor Nutlin-3 to restore p53, we corrected the defective self-renewal properties of Numb-deficient CSCs and inhibited CSC expansion, with a marked effect on tumorigenicity and metastasis. Remarkably, a regimen combining Nutlin-3 and chemotherapy induced persistent tumor growth inhibition, or even regression, and prevented CSC-driven tumor relapse after removal of chemotherapy. Our data provide a pre-clinical proof-of-concept that targeting Numb/p53 results in a specific anti-CSC therapy in human BCs.
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Tosoni
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pambianco
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
authors.forename: Blanche
authors.initials: B
authors.lastname: Ekalle Soppo
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zecchini
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bertalot
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.|Dipartimento di Oncologia e Emato-oncologia, Università degli Studi di Milano, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.|Dipartimento di Oncologia e Emato-oncologia, Università degli Studi di Milano, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy pierpaolo.difiore@ifom.eu salvatore.pece@ieo.it.|IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.|Dipartimento di Oncologia e Emato-oncologia, Università degli Studi di Milano, Milan, Italy.
authors.forename: Pier Paolo
authors.identifier: 0000-0002-2252-0950
authors.initials: PP
authors.lastname: Di Fiore
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy pierpaolo.difiore@ifom.eu salvatore.pece@ieo.it.|Dipartimento di Oncologia e Emato-oncologia, Università degli Studi di Milano, Milan, Italy.
authors.forename: Salvatore
authors.identifier: 0000-0003-1764-3929
authors.initials: S
authors.lastname: Pece
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007093:Imidazoles; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D017239:Paclitaxel
keywords: Numb; breast cancer; cancer stem cells; p53; primary‐derived xenografts