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
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