ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome

Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Cell Stem Cell (Impact Factor: 22.15). 12/2007; 1(5):555-67. DOI: 10.1016/j.stem.2007.08.014
Source: PubMed

ABSTRACT Application of stem cell biology to breast cancer research has been limited by the lack of simple methods for identification and isolation of normal and malignant stem cells. Utilizing in vitro and in vivo experimental systems, we show that normal and cancer human mammary epithelial cells with increased aldehyde dehydrogenase activity (ALDH) have stem/progenitor properties. These cells contain the subpopulation of normal breast epithelium with the broadest lineage differentiation potential and greatest growth capacity in a xenotransplant model. In breast carcinomas, high ALDH activity identifies the tumorigenic cell fraction, capable of self-renewal and of generating tumors that recapitulate the heterogeneity of the parental tumor. In a series of 577 breast carcinomas, expression of ALDH1 detected by immunostaining correlated with poor prognosis. These findings offer an important new tool for the study of normal and malignant breast stem cells and facilitate the clinical application of stem cell concepts.

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Available from: Gabriela Dontu, Jul 26, 2015
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    • "Combinations of cell surface markers that have been used to detect cell populations enriched in these properties include CD49f high EpCAM low (Eirew et al., 2008; Lim et al., 2009), CD73+CD90– (Roy et al., 2013), CD10+ (Keller et al., 2012), and CD49f+DLL1+DNER+ (Pece et al., 2010). Functional properties used to identify stem cells are high aldehyde dehydrogenase (ALDH) activity (Ginestier et al., 2007) and the ability to survive and proliferate in anchorage-independent conditions (Dontu et al., 2003; Pece et al., 2010). Some of these markers (i.e., ALDH+ and CD49f+) correlate with poor clinical outcome when highly expressed in breast tumors (Ali et al., 2011; Ginestier et al., 2007), possibly because they also identify a cancer stem cell population. "
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    Stem Cell Reports 03/2015; DOI:10.1016/j.stemcr.2015.02.013
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    • "CSCs have the capability of being resistant to chemotherapy and radiotherapy by many molecular mechanisms. For example, it has been established that increases in the aldehyde dehydrogenase (ALDH) activity in CSC seem to mediate their resistance to particular chemotherapeutics (Hilton 1984; Ginestier et al. 2007). Additionally, CSCs chemo/radiotherapy resistance is depicted to be reliant on interleukin-4 (IL-4) signaling pathway since upregulation of IL-4 on these cells results in resistance to apoptosis (Francipane et al. 2008). "
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    • "Interestingly, BCC 199a and BCC 199a/214 displayed enhanced resistance to suspension-induced cell death in a minimal serum tumbling assay, exhibiting >50% survival rates after 24 hr of suspension, and a corresponding >50% reduction in their apoptosis rates as measured by 7-aminoactinomycin D (7AAD; Figure 2D). In addition , BCC 199a and BCC 199a/214 displayed increased abilities to grow in low-attachment mammosphere growth conditions after serial passages (Figure 2E), and they showed multifold increases in the expression levels of the CSC-associated marker ALDH1 (Ginestier et al., 2007), as determined by rtPCR (Figure S2G) and by ALDEFLUOR-based FACS assays (Figures 2F). Most importantly, however, BCC 199a and BCC 199a/214 possessed markedly enhanced tumor-initiating capabilities in limiting-dilution tumor assays in Nude mice, forming tumors at 100 cells per injection at $2–3 times the rate of their BCC null controls (Figure 2G). "
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