Identification and characterization of cancer initiating cells from BRCA1 related mammary tumors using markers for normal mammary stem cells.
It is hypothesized that cancer stem cells arise either from normal stem cells or from progenitor cells that have gained the ability to self-renew. Here we determine whether mammary cancer stem cells can be isolated by using antibodies that have been used for the isolation of normal mammary stem cells. We show that BRCA1 mutant cancer cell lines contained a subpopulation of CD24+CD29+ or CD24+CD49f+ cells that exhibited increased proliferation and colony forming ability in vitro, and enhanced tumor-forming ability in vivo. The purified CD24+CD29+ cells could differentiate and reconstitute the heterogeneity found in parental cells when plated as a monolayer. Under low-attachment conditions, we detected "tumorspheres" only in the presence of double positive cells, which maintained their ability to self-renew. Furthermore, CD24+CD29+ cells could form tubular structures reminiscent of the mammary ductal tree when grown in three-dimensional cultures, implying that these cancer cells maintain some of the characteristics of the normal stem cells. Nevertheless, they could still drive tumor formation since as low as 500 double positive cells immediately after sorting from BRCA1 mutant primary tumors were able to form tumors with the same heterogeneity found in the original tumors. These data provide evidence that breast cancer stem cells originate from normal stem cells and advance our understanding of BRCA1-associated tumorigenesis with possible implications for future cancer treatment.
Vassilopoulos
Athanassios
A
Genetics of Development, Disease Branch, National Institute of Diabetes, Digestive, Kidney Diseases, National Institutes of Health, Bethesda, Maryland, MD 20892, USA.
Wang
Rui-Hong
RH
Petrovas
Constantinos
C
Ambrozak
David
D
Koup
Richard
R
Deng
Chu-Xia
CX
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D051927:CD24 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D013234:Stem Cells / Q000378:metabolism*
D019313:BRCA1 Protein; D015415:Biomarkers; D051927:CD24 Antigen; C497889:CD24 protein, human; D019012:Integrin beta1