title: Repression of mammary stem/progenitor cells by p53 is mediated by Notch and separable from apoptotic activity.
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 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.affiliation: Molecular and Cellular Biology Program, University of Massachusetts-Amherst, Massachusetts, USA.
authors.forename: Luwei
authors.initials: L
authors.lastname: Tao
authors.forename: Amy L
authors.initials: AL
authors.lastname: Roberts
authors.forename: Karen A
authors.initials: KA
authors.lastname: Dunphy
authors.forename: Carol
authors.initials: C
authors.lastname: Bigelow
authors.forename: Haoheng
authors.initials: H
authors.lastname: Yan
authors.forename: D Joseph
authors.initials: DJ
authors.lastname: Jerry
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D016158:Genes, p53 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics / Q000473:pathology / Q000628:therapy; D042361:Mammary Glands, Human / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases