Our previous work demonstrated, in preclinical models, that targeting NUMB/p53 LOF in NUMB‐deficient BCs using the MDM2 inhibitor, Nutlin‐3, to restore functional p53, is an efficient anti‐CSC therapy.[1m] However, despite intense research, clinical use of MDM2 inhibitors has been hampered by their limited clinical efficacy and associated toxicities.[26] In this study, by elucidating the mechanism of aberrant NUMB degradation in BC, we have highlighted an additional point of therapeutic intervention in the NUMB/p53 pathway. The gene discussed is NUMB; the disease is breast cancer.