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BIOLOGICAL SCIENCES / CELL BIOLOGY
Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts

Kathryn B. Horwitz^*,, Wendy W. Dye^*, Joshua Chuck Harrell^*, Peter Kabos, and Carol A. Sartorius^*,

*Divisions of Endocrinology and Medical Oncology, Department of Medicine, and Department of Pathology, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO 80045

Edited by Irving L. Weissman, Stanford University School of Medicine, Stanford, CA, and approved February 20, 2008 (received for review July 2, 2007)

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.

cancer stem cell | cytokeratin 5 | estrogen receptor | progesterone receptor

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0706216105/DCSupplemental.

To whom correspondence should be addressed. E-mail: carol.sartorius{at}uchsc.edu

© 2008 by The National Academy of Sciences of the USA

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