title: Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts.
abstract: There are two major subtypes of human breast cancers: the luminal, estrogen, and progesterone receptor-positive, cytokeratin 18-positive (ER(+)PR(+)CK18(+)) subtype, and the basal ER(-)PR(-)CK18(-)CK5(+) subtype. Tumor-initiating cells (CD44(+)) have been described for human breast cancers; whether these are common to the two subtypes is unknown. We have identified a rare population of cells that are both CD44(+) and ER(-)PR(-)CK5(+) in luminal-like ER(+)PR(+) T47D human breast tumor xenografts. The tumor-isolated CD44(+) cell fraction was highly enriched for clonogenic (in vitro culture) and tumorigenic (in vivo reimplantation) cells compared with the CD44(-) cell fraction. Rare ER(-)PR(-)CK5(+) cells were present within CD44(+)-derived colonies. Tumor-isolated cells placed in minimal media also contained rare ER(-)PR(-)CK5(+) cells at early time points (<10 cells); however, this population did not expand with increasing colony size. The number of ER(+)PR(+)CK5(-) cells, conversely, increased linearly with colony growth. Similary, tumors originating in vivo from CD44(+) cells contained a rare static ER(-)PR(-)CK5(+) population, an intermediate ER(-)PR(-)CK5(-) population, and an expanding ER(+)PR(+)CK5(-) population. Putative ER(+)PR(+)CK5(+) transitional cells could be seen only in colonies or tumors treated with a progestin. We propose that luminal ER(+)PR(+) breast tumors contain a minor ER(-)PR(-)CK5(+) population that has the capacity to generate the majority of ER(+)PR(+)CK18(+)CK5(-) cells. Luminal breast cancers are treated with endocrine therapies that target ER. The rare ER(-)PR(-)CK5(+) progenitor cells would escape such treatments and survive to repopulate the tumor.
authors.affiliation: Divisions of Endocrinology and Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO 80045, USA.
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Horwitz
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Dye
authors.forename: Joshua Chuck
authors.initials: JC
authors.lastname: Harrell
authors.forename: Peter
authors.initials: P
authors.lastname: Kabos
authors.forename: Carol A
authors.initials: CA
authors.lastname: Sartorius
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000737:chemistry / Q000145:classification / Q000473:pathology*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors; D051379:Mice; D009374:Neoplasms, Experimental; D011960:Receptors, Estrogen / Q000172:deficiency*; D011980:Receptors, Progesterone / Q000172:deficiency*; D014183:Transplantation, Heterologous
chemical_list: D018960:Hyaluronan Receptors; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone