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.
journal_name
EMBO Mol Medjournal_title
EMBO molecular medicineauthors
Tosoni D,Pambianco S,Ekalle Soppo B,Zecchini S,Bertalot G,Pruneri G,Viale G,Di Fiore PP,Pece Sdoi
10.15252/emmm.201606940subject
Has Abstractpub_date
2017-05-01 00:00:00pages
655-671issue
5eissn
1757-4676issn
1757-4684pii
emmm.201606940journal_volume
9pub_type
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