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Breast cancer is the most common tumor among women with inherited mutations in the  p53  gene (Li‐Fraumeni syndrome). The tumors represent the basal‐like subtype, which has been suggested to originate from mammary stem/progenitor cells. In mouse mammary epithelium, mammosphere‐forming potential was increased with decreased dosage of the gene encoding the p53 tumor suppressor protein ( Trp53 ). Limiting dilution transplantation also showed a 3.3‐fold increase in the frequency of long‐term regenerative mammary stem cells in  Trp53 −/− mice. The repression of mammospheres by p53 was apparent despite the absence of apoptotic responses to radiation indicating a dissociation of these two activities of p53. The effects of p53 on progenitor cells were also observed in TM40A cells using both mammosphere‐forming assays and the DsRed‐let7c‐sensor. The frequency of long‐term label‐retaining epithelial cells was decreased in  Trp53 −/− mammary glands indicating that asymmetric segregation of DNA is diminished and contributes to the expansion of the mammary stem cells. Treatment with an inhibitor of γ‐secretase ( N ‐[ N ‐(3,5‐difluorophenacetyl)‐ L ‐alanyl]‐ S ‐phenylglycine  t ‐butyl ester) reduced the number of  Trp53 −/− mammospheres to the level found in  Trp53 +/+ cells. These results demonstrate that basal levels of p53 restrict mammary stem/progenitor cells through Notch and that the Notch pathway is a therapeutic target to prevent expansion of this vulnerable pool of cells. S TEM  C ELLS  2011;29:119–127

Repression of Mammary Stem/Progenitor Cells by p53 Is Mediated by Notch and Separable from Apoptotic Activity