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.