Pre-clinical validation of a selective anti-cancer stem cell therapy for Numb-deficient human breast cancers

Daniela Tosoni, Sarah Pambianco, Blanche Ekalle Soppo, Silvia Zecchini, Giovanni Bertalot, Giancarlo Pruneri, Giuseppe Viale, Pier Paolo Di Fiore, Salvatore Pece

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)655-671
Number of pages17
JournalEMBO Molecular Medicine
Volume9
Issue number5
DOIs
Publication statusPublished - May 1 2017

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Keywords

  • breast cancer
  • cancer stem cells
  • Numb
  • p53
  • primary-derived xenografts

ASJC Scopus subject areas

  • Molecular Medicine

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