Document Detail


Repression of mammary stem/progenitor cells by p53 is mediated by Notch and separable from apoptotic activity.
MedLine Citation:
PMID:  21280161     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Luwei Tao; Amy L Roberts; Karen A Dunphy; Carol Bigelow; Haoheng Yan; D Joseph Jerry
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  29     ISSN:  1549-4918     ISO Abbreviation:  Stem Cells     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-31     Completed Date:  2011-05-02     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  United States    
Other Details:
Languages:  eng     Pagination:  119-27     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 AlphaMed Press.
Affiliation:
Molecular and Cellular Biology Program, University of Massachusetts-Amherst, Massachusetts, USA.
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MeSH Terms
Descriptor/Qualifier:
Amyloid Precursor Protein Secretases / antagonists & inhibitors
Animals
Apoptosis*
Breast Neoplasms / genetics,  pathology,  prevention & control
Cells, Cultured
Dipeptides / pharmacology
Epithelial Cells / physiology
Female
Genes, p53 / genetics,  physiology*
Humans
Li-Fraumeni Syndrome / genetics,  pathology,  therapy
Mammary Glands, Human / cytology*,  drug effects,  metabolism
Mice
Mice, Inbred BALB C
Receptors, Notch / antagonists & inhibitors,  metabolism*
Stem Cell Transplantation
Stem Cells / drug effects,  metabolism,  physiology*
Grant Support
ID/Acronym/Agency:
R01 CA095164/CA/NCI NIH HHS; R01 CA105452/CA/NCI NIH HHS; R01 ES015739/ES/NIEHS NIH HHS; R01-CA095164/CA/NCI NIH HHS; R01-CA105452/CA/NCI NIH HHS; R01-ES015739/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Dipeptides; 0/N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; 0/Receptors, Notch; EC 3.4.-/Amyloid Precursor Protein Secretases
Comments/Corrections

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