Aldehyde Dehydrogenase Activity Is a Biomarker of Primitive Normal Human Mammary Luminal Cells

Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Stem Cells (Impact Factor: 6.52). 02/2012; 30(2):344-8. DOI: 10.1002/stem.1001
Source: PubMed


Elevated aldehyde dehydrogenase (ALDH) expression/activity has been identified as an important biomarker of primitive cells in various normal and malignant human tissues. Here we examined the level and type of ALDH expression and activity in different subsets of phenotypically and functionally defined normal human mammary cells. We find that the most primitive human mammary stem and progenitor cell types with bilineage differentiation potential show low ALDH activity but undergo a marked, selective, and transient upregulation of ALDH activity at the point of commitment to the luminal lineage. This mirrors a corresponding change in transcripts and protein levels of ALDH1A3, an enzyme involved in retinoic acid synthesis and the most highly expressed ALDH gene in normal human mammary tissue. In contrast, ALDH1A1 is expressed at low levels in all mammary epithelial cells. These findings raise interesting questions about the reported association of ALDH activity with breast cancer stem cells and breast cancer prognosis.

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Available from: Nagarajan (Raj) Kannan, Oct 09, 2014
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    • "To overcome this limitation, we used a luminal breast cancer cell line, MCF7, as a source for ALDH+ and CD44+CD24-breast CSCs since most cell lines contain both CSC fractions [18] [19] [20]. Within the MCF7 cell line, most cells exhibit a mature luminal cell phenotype, CD49f-EpCAM+ [21] [22] [23]. If breast CSCs are more prognostic than bulk cancer cells, the proteins governing stem cell properties are likely to influence clinical outcome. "
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    ABSTRACT: Accumulating evidence has demonstrated that breast cancers are initiated and develop from a small population of stem-like cells termed cancer stem cells (CSCs). These cells are hypothesized to mediate tumor metastasis and contribute to therapeutic resistance. However, the molecular regulatory networks responsible for maintaining CSCs in an undifferentiated state have yet to be elucidated. In this study, we used CSC markers to isolate pure breast CSCs fractions (ALDH+ and CD44+CD24- cell populations) and the mature luminal cells (CD49f-EpCAM+) from the MCF7 cell line. Proteomic analysis was performed on these samples and a total of 3,304 proteins were identified. A label-free quantitative method was applied to analyze differentially expressed proteins. Using the criteria of greater than 2 fold changes and p value < 0.05, 305, 322 and 98 proteins were identified as significantly different in three pairwise comparisons of ALDH+ vs CD44+CD24-, ALDH+ vs CD49f-EpCAM+ and CD44+CD24- vs CD49f-EpCAM+, respectively. Pathway analysis of differentially expressed proteins by Ingenuity Pathway Analysis (IPA) revealed potential molecular regulatory networks that may regulate CSCs. Selected differential proteins were validated by Western blot assay and immunohistochemical staining. The use of proteomics analysis may increase our understanding of the underlying molecular mechanisms of breast CSCs. This may be of importance in the future development of anti-CSC therapeutics. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2015 · Proteomics
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    • "*Author for correspondence ( luminal epithelium, converts a colorless substrate into a green fluorescent product (Fig. 1D) (Ginestier et al., 2007; Eirew et al., 2012). ALDH + progenitor cells readily formed hollow cysts after 15 days culture on Matrigel, whereas ALDH − cells did not, indicating that the cyst-forming ability of MECs arises from ALDH + progenitors (Fig. 1E-G). "
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    ABSTRACT: FGF signaling is essential for mammary gland development, yet the mechanisms by which different members of the FGF family control stem cell function and epithelial morphogenesis in this tissue are not well understood. Here, we have examined the requirement of Fgfr2 in mouse mammary gland morphogenesis using a postnatal organ regeneration model. We found that tissue regeneration from basal stem cells is a multistep event, including luminal differentiation and subsequent epithelial branching morphogenesis. Basal cells lacking Fgfr2 did not generate an epithelial network owing to a failure in luminal differentiation. Moreover, Fgfr2 null epithelium was unable to undergo ductal branch initiation and elongation due to a deficiency in directional migration. We identified FGF10 and FGF2 as stromal ligands that control distinct aspects of mammary ductal branching. FGF10 regulates branch initiation, which depends on directional epithelial migration. By contrast, FGF2 controls ductal elongation, requiring cell proliferation and epithelial expansion. Together, our data highlight a pleiotropic role of Fgfr2 in stem cell differentiation and branch initiation, and reveal that different FGF ligands regulate distinct aspects of epithelial behavior.
    Full-text · Article · Jul 2014 · Development
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    • "Although the exact isoform of ALDH1A responsible for the enzymatic activity assessed by BODIPY aminoacetaldehyde remains controversial [13-16], aldehyde dehydrogenase 1 family member A1 (ALDH1A1) is thought to have a predominant role [17]. Thus, much attention has been focused on the relationship between the expression of this isoform and the clinicopathologic parameters, including prognosis, of breast cancer patients. "
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    ABSTRACT: Background Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) has been identified as a putative cancer stem cell (CSC) marker in breast cancer. However, the clinicopathological and prognostic significance of this protein in breast cancer patients remains controversial. Methods This meta-analysis was conducted to address the above issues using 15 publications covering 921 ALDH1A1+ cases and 2353 controls. The overall and subcategory analyses were performed to detect the association between ALDH1A1 expression and clinicopathological/prognostic parameters in breast cancer patients. Results The overall analysis showed that higher expression of ALDH1A1 is associated with larger tumor size, higher histological grade, greater possibility of lymph node metastasis (LNM), higher level expression of epidermal growth factor receptor 2 (HER2), and lower level expression of estrogen receptor (ER)/progesterone receptor (PR). The prognosis of breast cancer patients with ALDH1A1+ tumors was poorer than that of the ALDH1A1- patients. Although the relationships between ALDH1A1 expression and some clinicopathological parameters (tumor size, LNM, and the expression of HER2) was not definitive to some degree when we performed a subcategory analysis, the predictive values of ALDH1A1 expression for histological grade and survival of breast cancer patients were significant regardless of the different cutoff values of ALDH1A1 expression, the different districts where the patients were located, the different clinical stages of the patients, the difference in antibodies used in the studies, and the surgery status. Conclusions Our results indicate that ALDH1A1 is a biomarker to predict tumor progression and poor survival of breast cancer patients. This marker should be taken into consideration in the development of new diagnostic and therapeutic program for breast cancer.
    Full-text · Article · Jun 2014 · BMC Cancer
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