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: 22.27). 12/2007; 1(5):555-67. DOI: 10.1016/j.stem.2007.08.014
Source: PubMed


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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    • "CSC can also be identified by specific biomarkers in vitro in many types of cancer. Widely used biomarkers for characterizing breast CSC include elevated aldehyde dehydrogenase (ALDH) activity (Ginestier et al., 2007), CD133 + (Wright et al., 2008), and CD44 + /CD24 – (Al-Hajj et al., 2003). Breast CSC can also be propagated in vitro as mammospheres, which are spherical clusters of cells in non-adherent culture conditions (Ponti et al., 2005). "
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    ABSTRACT: The mesoderm- and epithelial-mesenchymal transition-associated transcription factor FOXC1 is specifically overexpressed in basal-like breast cancer (BLBC), but its biochemical function is not understood. Here we demonstrate that FOXC1 controls cancer stem cell (CSC) properties enriched in BLBC cells via activation of Smoothened (SMO)-independent Hedgehog (Hh) signaling. This non-canonical activation of Hh is specifically mediated by Gli2. We further show that the N-terminal domain of FOXC1 (aa 1-68) binds directly to an internal region (aa 898-1168) of Gli2, enhancing the DNA-binding and transcription-activating capacity of Gli2. FOXC1 expression correlates with that of Gli2 and its targets in human breast cancers. Moreover, FOXC1 overexpression reduces sensitivity to anti-Hedgehog (Hh) inhibitors in BLBC cells and xenograft tumors. Together, these findings reveal FOXC1-mediated non-canonical Hh signaling that determines the BLBC stem-like phenotype and anti-Hh sensitivity, supporting inhibition of FOXC1 pathways as potential approaches for improving BLBC treatment.
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    • "Al- Hajj et al. (2003) were the first to show that tumor-initiating cells were capable of recapitulating the original tumor phenotype when transplanted into immunodeficient mice. In vitro functional assays for BC stem cell (BCSC) activity include aldehyde dehydrogenase 1 (ALDH1) enzyme activity and the capacity to form clonogenic mammospheres in suspension culture (Ginestier et al., 2007). It has been demonstrated that the BCSC population is ER negative/low and resistant to the direct effects of endocrine therapy (Simõ es et al., 2011; Harrison et al., 2013; Piva et al., 2014). "
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    Cell Reports 09/2015; 12(12). DOI:10.1016/j.celrep.2015.08.050 · 8.36 Impact Factor
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    • "Characteristics by mAb and IFN-g Molecular analyses in vitro revealed that the ordered treatment of breast tumor cells with anti-erbB2/neu mAb and IFN-g diminished expression of Snail proteins, which mediates stem-cell-like properties. ALDH1 expression patterns also define cancer stem cell phenotypes, and its expression correlates with breast cancer prognostic features (Douville et al., 2009; Ginestier et al., 2007). We compared tumors at the end of treatment for ALDH1 levels. "
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