Accession Number : ADA551933


Title :   Regulation of Mammary Progenitor Cells by p53 and Parity


Descriptive Note : Annual summary rept. 1 Jan 2010-31 Dec 2010


Corporate Author : MASSACHUSETTS UNIV AMHERST


Personal Author(s) : Tao, Luwei ; Jerry, D J


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a551933.pdf


Report Date : Jan 2011


Pagination or Media Count : 36


Abstract : 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 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 stem/progenitor cells through Notch and that the Notch pathway is a therapeutic target to prevent expansion of this vulnerable pool of cells.


Descriptors :   *BREAST CANCER , *EPITHELIUM , *GENES , *PARITY , *STEM CELLS , CELLS(BIOLOGY) , DOSAGE , IN VITRO ANALYSIS , INHIBITORS , IONIZING RADIATION , MAMMARY GLANDS , NEOPLASMS , RESPONSE(BIOLOGY) , SEGREGATION(METALLURGY) , THERAPY , TRANSPLANTATION


Subject Categories : Genetic Engineering and Molecular Biology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE