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Date of Award
9-2011
Access Type
Campus Access
Document type
dissertation
Degree Name
Doctor of Philosophy (PhD)
Degree Program
Molecular and Cellular Biology
First Advisor
D. Joseph Jerry
Second Advisor
Jesse Mager
Third Advisor
Sallie Smith Schneider
Subject Categories
Cell Biology | Genetics | Molecular Biology
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 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 (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. Treatment with an inhibitor of γ-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. Notch is a target of γ-secretase suggesting that the Notch pathway is a therapeutic target to prevent expansion of this vulnerable pool of cells. The expansion of p53-deficient mammary stem/progenitor cells can also be reversed after the expression of C-terminal p53, suggesting that the C-terminal domains of p53 may be responsible for the regulation of mammary stem/progenitor cells self-renewal. In parous mammary gland, increased p53 responsiveness sensitized mammary stem/progenitor cells to ionizing radiation without affecting the self-renewal of these cells, which may be responsible for the parity-induced protection against breast cancer.
DOI
https://doi.org/10.7275/5686227
Recommended Citation
Tao, Luwei, "Regulation Of Mammary Stem/Progenitor Cells By P53 And Parity" (2011). Doctoral Dissertations 1896 - February 2014. 322.
https://doi.org/10.7275/5686227
https://scholarworks.umass.edu/dissertations_1/322