Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts

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.