Using patient‐derived xenografts (PDX), as a clinically relevant model of Numb‐deficient breast cancers (BC), we show that the unlimited self‐renewal and high tumorigenic potential of CSCs in Numb‐deficient BCs can be selectively reverted by re‐expression of the tumor suppressor Numb, or pharmacological restoration of p53 function with the Mdm2 inhibitor Nutlin‐3. Here, MDM2 is linked to breast cancer.