Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts (original) (raw)
2008, Proceedings of the National Academy of Sciences
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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