02194nas a2200193   4500008004100000245011500041210006900156260001300225300001100238490000700249520148500256100001501741700002001756700002101776700001901797700001701816700001801833856014901851       2011                        eng d00aRepression of mammary stem/progenitor cells by p53 is mediated by Notch and separable from apoptotic activity.0 aRepression of mammary stemprogenitor cells by p53 is mediated by  c2011 Jan  a119-270 v293 a<p>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.</p>
1 aTao, Luwei1 aRoberts, Amy, L1 aDunphy, Karen, A1 aBigelow, Carol1 aYan, Haoheng1 aJerry, Joseph  uhttps://www.umass.edu/veterinary-animal-sciences/research-faculty/publications/repression-of-mammary-stem-progenitor-cells-by-p53-is-mediated-by