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Regulation of Mammary Progenitor Cells by p53 and Parity

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Annual summary rept. 1 Jan 2010-31 Dec 2010

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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 stemprogenitor 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 frequency of long-term label-retaining epithelial cells LRECs was decreased in Trp53-- mammary glands indicating that asymmetric segregation of DNA is diminished and contributes to the expansion of the mammary stem cells. Progenitor cell was also labeled with let-7c sensor. The knockdown of p53 also significantly increased the number of DsR progenitor cells in vitro. Treatment with an inhibitor of gama-secretase DAPT reduced the number of Trp53-- mammospheres to the level found in Trp53 cells. These results demonstrate that basal levels of p53 restrict mammary stemprogenitor cells through Notch and that the Notch pathway is a therapeutic target to prevent expansion of this vulnerable pool of cells.

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  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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