Abstract
IntroductionWhether cancer stem cells occur in BRCA1-associated breast cancer and contribute to therapeutic response is not known.MethodsWe generated and characterized 16 cell lines from five distinct Brca1deficient mouse mammary tumors with respect to their cancer stem cell characteristics.ResultsAll cell lines derived from one tumor included increased numbers of CD44+/CD24- cells, which were previously identified as human breast cancer stem cells. All cell lines derived from another mammary tumor exhibited low levels of CD44+/CD24- cells, but they harbored 2% to 5.9% CD133+ cells, which were previously associated with cancer stem cells in other human and murine tumors. When plated in the absence of attachment without presorting, only those cell lines that were enriched in either stem cell marker formed spheroids, which were further enriched in cells expressing the respective cancer stem cell marker. In contrast, cells sorted for CD44+/CD24- or CD133+ markers lost their stem cell phenotype when cultured in monolayers. As few as 50 to 100 CD44+/CD24- or CD133+ sorted cells rapidly formed tumors in nonobese diabetic/severe combined immunodeficient mice, whereas 50-fold to 100-fold higher numbers of parental or stem cell depleted cells were required to form few, slow-growing tumors. Expression of stem cell associated genes, including Oct4, Notch1, Aldh1, Fgfr1, and Sox1, was increased in CD44+/CD24- and CD133+ cells. In addition, cells sorted for cancer stem cell markers and spheroid-forming cells were significantly more resistant to DNA-damaging drugs than were parental or stem cell depleted populations, and they were sensitized to the drugs by the heat shock protein-90 inhibitor 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride).ConclusionBrca1-deficient mouse mammary tumors harbor heterogeneous cancer stem cell populations, and CD44+/CD24- cells represent a population that correlates with human breast cancer stem cells.
Highlights
Whether cancer stem cells occur in BRCA1associated breast cancer and contribute to therapeutic response is not known
Brca1-deficient mouse mammary tumors harbor heterogeneous cancer stem cell populations, and CD44+/ CD24- cells represent a population that correlates with human breast cancer stem cells
Characterization of cell lines from Brca1 mouse mammary tumors Sixteen cell lines were generated from five independent original Brca1Δexon11/p53+/- mouse mammary tumors [15,16]
Summary
Whether cancer stem cells occur in BRCA1associated breast cancer and contribute to therapeutic response is not known. BRCA1 was the first identified breast cancer susceptibility gene and was localized to 17q21 by positional cloning more than 15 years ago [1]. BRCA1 mutation is associated with a high incidence of bilateral disease, and confers an 82% risk for developing breast cancer and an 54% risk for developing ovarian cancer by age 80 years [2]. Somatic mutations of BRCA1 have been reported in up to 10% of cases of sporadic ovarian cancer, but they are extremely rare in sporadic breast cancer [3,4,5]. The existence of cancer stem cells associated with BRCA1 mutations or downregulation has not been reported
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