Pre-clinical Validation of a Selective Anti-cancer Stem Cell Therapy for Numb-deficient Human Breast Cancers

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2017 Mar 17

PMID 28298340

Citations 26

Authors

Daniela Tosoni

Sarah Pambianco

Blanche Ekalle Soppo

Silvia Zecchini

Giovanni Bertalot

Giancarlo Pruneri

Giuseppe Viale

Pier Paolo Di Fiore

Salvatore Pece

Affiliations

Soon will be listed here.

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.

Citing Articles

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