Open AccessPre‐clinical validation of a selective anti‐cancer stem cell therapy for Numb‐deficient human breast cancers
Author(s) -
Tosoni Daniela,
Pambianco Sarah,
Ekalle Soppo Blanche,
Zecchini Silvia,
Bertalot Giovanni,
Pruneri Giancarlo,
Viale Giuseppe,
Di Fiore Pier Paolo,
Pece Salvatore
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201606940
Subject(s) - numb , cancer research , breast cancer , human breast , cancer , medicine , stem cell , oncology , biology , microbiology and biotechnology
The cell fate determinant Numb is frequently downregulated in human breast cancers ( BC s), 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 ( CSC s). 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 BC s 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 BC s. In these cancers, using the inhibitor Nutlin‐3 to restore p53, we corrected the defective self‐renewal properties of Numb‐deficient CSC s 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 BC s.