CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer.
Defining the populations of tumor-initating cells that are present in tumors is a first step in developing therapeutics to target these cells. We show here that both CD44(pos)CD24(neg) and CD44(pos)CD24(pos) cell populations in estrogen receptor (ER) alpha-negative breast tumors are tumorigenic in murine xenograft models. We also describe a third population of xenograft-initiating cells (XIC) enriched in CD44(pos)CD49f(hi)CD133/2(hi) cells that display heightened tumorigenicity, self-renewal in vivo, and the capacity to give rise to functional and molecular heterogeneity. Consistent with their capacity for self-renewal, these cells express elevated levels of Sox2, Bmi-1, and/or Nanog and their CpG islands are hypermethylated relative to nontumorigenic cells. These differences in methylome regulation may be responsible for the dramatic functional differences between the two populations. The identification of CD44(pos)CD49f(hi)CD133/2(hi) XIC in ER-negative tumors may lead to expanded understanding of these tumors and ultimately the development of therapeutics designed to specifically target the cells.
Meyer
Matthew J
MJ
Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4254, USA.
Fleming
Jodie M
JM
Lin
Amy F
AF
Hussnain
S Amal
SA
Ginsburg
Erika
E
Vonderhaar
Barbara K
BK
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D016130:Immunophenotyping; D039503:Integrin alpha6 / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010455:Peptides / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous
D000071916:AC133 Antigen; D015703:Antigens, CD; D047628:Estrogen Receptor alpha; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D039503:Integrin alpha6; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; C497483:CD44 protein, human; C000606023:PROM1 protein, human; C000606024:Prom1 protein, mouse