Identification of tumor-initiating cells in a p53-null mouse model of breast cancer.
Using a syngeneic p53-null mouse mammary gland tumor model that closely mimics human breast cancer, we have identified, by limiting dilution transplantation and in vitro mammosphere assay, a Lin(-)CD29(H)CD24(H) subpopulation of tumor-initiating cells. Upon subsequent transplantation, this subpopulation generated heterogeneous tumors that displayed properties similar to the primary tumor. Analysis of biomarkers suggests the Lin(-)CD29(H)CD24(H) subpopulation may have arisen from a bipotent mammary progenitor. Differentially expressed genes in the Lin(-)CD29(H)CD24(H) mouse mammary gland tumor-initiating cell population include those involved in DNA damage response and repair, as well as genes involved in epigenetic regulation previously shown to be critical for stem cell self-renewal. These studies provide in vitro and in vivo data that support the cancer stem cell (CSC) hypothesis. Furthermore, this p53-null mouse mammary tumor model may allow us to identify new CSC markers and to test the functional importance of these markers.
Department of Molecular and Cellular Biology, Graduate program in Translational Biology and Molecular Medicine, and Lester and Sue Smith Breast Center of Baylor College of Medicine, Houston, Texas, USA.
Mei
M
Zhang
Fariba
F
Behbod
Rachel L
RL
Atkinson
Melissa D
MD
Landis
Frances
F
Kittrell
David
D
Edwards
Daniel
D
Medina
Anna
A
Tsimelzon
Susan
S
Hilsenbeck
Jeffrey E
JE
Green
Aleksandra M
AM
Michalowska
Jeffrey M
JM
Rosen
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D017690:Cell Transplantation; D003114:Colony-Forming Units Assay; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006720:Homozygote; D007124:Immunoenzyme Techniques; D019012:Integrin beta1 / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells; D009713:Nucleotidyltransferases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D014408:Biomarkers, Tumor; D051927:CD24 Antigen; D019012:Integrin beta1; D016159:Tumor Suppressor Protein p53; D009713:Nucleotidyltransferases; C057535:lincosaminide O-nucleotidyltransferase