CD44/CD24 cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome

Department of Pathology, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA.
Human pathology (Impact Factor: 2.81). 08/2011; 43(3):364-73. DOI: 10.1016/j.humpath.2011.05.005
Source: PubMed

ABSTRACT Women classified as having triple-negative tumors have a poor prognosis. The importance of CD44(+)/CD24(-/low) (stem/progenitor cell-phenotype) in breast cancer patients has also been appreciated. However, correlation between triple negativity and CD44(+)/CD24(-/low) with tumor recurrence remains elusive. In the present study, we evaluated tumor specimens of 50 breast cancer patients with known hormone receptor status for whom we had follow-up information and outcome data available, and performed immunohistochemistry analysis to determine CD44 and CD24 expression. Gene expression arrays were also independently performed on 52 breast cancer specimens with banked frozen tissue. Lastly, we used FVBN202 transgenic mouse model of breast carcinoma and determined the hormone receptor status, the proportion of CD44(+)/CD24(-/low) breast cancer stem-like cells, and the behavior of the tumor. We determined that patients with triple-negative tumors had significantly higher incidence of recurrence or distant metastasis associated with increased frequency of breast cancer stem cell phenotypes compared with those with non-triple-negative tumors. Preclinical studies in FVBN202 transgenic mice confirmed these findings by showing that relapsed tumors were triple negative and had significantly higher frequency of breast cancer stem cells compared with their related primary tumors. Unlike non-triple-negative primary tumors, relapsed triple-negative tumors were tumorigenic at low doses when inoculated into FVBN202 transgenic mice. These findings suggest that CD44(+)/CD24(-/low) breast cancer stem-like cells play an important role in the clinical behavior of triple-negative breast cancer and that development of therapeutic targets directed to breast cancer stem-like cells may lead to reduction in the aggressiveness of triple-negative breast cancers.

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    • "Abrogation of Stat3 is integral to honokiol-mediated inhibition of EMT, invasion and migration of breast cancer cells Constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been reported in many malignancies , including breast cancer (Haura et al., 2005). Stat3, a DNA-binding transcription factor, regulates cell proliferation and survival, functions as a major player in driving the growth of breast cancer stem cells (Idowu et al., 2012; Marotta et al., 2011) and has been associated with epithelialemesenchymal transition of cancer cells and malignant progression (Berclaz et al., 2001; Colomiere et al., 2009; Haura et al., 2005). We sought to determine whether HNK modulates Stat3 phosphorylation and activation. "
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    ABSTRACT: Epithelial-mesenchymal transition (EMT), a critical step in the acquisition of metastatic state, is an attractive target for therapeutic interventions directed against tumor metastasis. Honokiol (HNK) is a natural phenolic compound isolated from an extract of seed cones from Magnolia grandiflora. Recent studies from our lab show that HNK impedes breast carcinogenesis. Here, we provide molecular evidence that HNK inhibits EMT in breast cancer cells resulting in significant downregulation of mesenchymal marker proteins and concurrent upregulation of epithelial markers. Experimental EMT induced by exposure to TGFβ and TNFα in spontaneously immortalized nontumorigenic human mammary epithelial cells is also completely reversed by HNK as evidenced by morphological as well as molecular changes. Investigating the downstream mediator(s) that may direct EMT-inhibition by HNK, we found functional interactions between HNK, Stat3, and EMT-signaling components. In vitro and in vivo analyses show that HNK inhibits Stat3 activation in breast cancer cells and tumors. Constitutive activation of Stat3 abrogates HNK-mediated activation of epithelial markers whereas inhibition of Stat3 using small molecule inhibitor, Stattic, potentiates HNK-mediated inhibition of EMT markers, invasion and migration of breast cancer cells. Mechanistically, HNK inhibits recruitment of Stat3 on mesenchymal transcription factor Zeb1 promoter resulting in decreased Zeb1 expression and nuclear translocation. We also discover that HNK increases E-cadherin expression via Stat3-mediated release of Zeb1 from E-cadherin promoter. Collectively, this study reports that HNK effectively inhibits EMT in breast cancer cells and provide evidence for a previously unrecognized cross-talk between HNK and Stat3/Zeb1/E-cadherin axis.
    Molecular oncology 05/2014; 8(3). DOI:10.1016/j.molonc.2014.01.004 · 5.94 Impact Factor
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    • "The prognostic significance of CD44?/CD24-phenotype is recently meticulously investigated, although the results remain controversial (Honeth et al. 2008; Abraham et al. 2005; Athanassiadou et al. 2009; Horiguchi et al. 2010; Idowu et al. 2012; Kim et al. 2011; Ricardo et al. 2011; Sung et al. 2010; Surowiak et al. 2006; Tanei et al. 2009), what might be caused by differences in clinical/histological characteristics of studied cases, treatment schedules applied or methods used for protein evaluation. It is also possible that parameters associated with tumour stroma remodelling (lymphocytic infiltration or expression of particular extracellular matrix components), or associated with tumour cell motility (fascin expression) as well as expression of basal markers (CK5/6, epidermal growth factor receptor [EGFR], P-cadherin, smooth muscle actin [SMA]), adhesion molecules (epithelial cell adhesion molecule Ep-CAM), or aberrant CK8/18 expression might help the CD44 ?/CD24-cells to form metastases or recurrent tumours. "
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    ABSTRACT: The hypothesis on cancer stem cells assumes the existence of small subpopulation of cells that possess the ability to undergo self-renewal and can give rise to the diversity of differentiated cells that form the tumour. It has been accepted that CD44(+)/CD24(-/low) phenotype is one of the features characterizing breast cancer stem cells. The aim of our study was to assess (1) prognostic significance of CD44/CD24 expression as well as (2) a relation between the above-mentioned phenotype and breast cancer subtypes [based on estrogen (ER), progesterone receptors, human epidermal growth factor receptor 2 and Ki67 status] and expression of selected markers such as fascin, laminin-5 gamma-2 chain, cytokeratin (CK) 5/6 and 8/18, epidermal growth factor receptor (EGFR), smooth muscle actin, P-cadherin and lymphocytic infiltration in invasive ductal breast cancer patients (T ≥ 1, N ≥ 1, M0), who underwent mastectomy followed by chemotherapy (with taxanes and/or anthracyclines) or/and hormonotherapy. We noted that most cancers with CD44-/CD24- and CD44-/CD24+ phenotype were ER positive. The majority of CD44-/CD24-, CD44-/CD24+ and CD44+/CD24- tumours were characterized by CK5/6 and EGFR negativity. In univariate analysis we demonstrated that patients with pN1/pN2 and with CD44 +/CD24- carcinomas had significantly lower risk of progression or cancer-related death than those with pN3 or tumours characterised by other CD44/CD24 expression patterns. We also found 100 % DFS in 12 patients with CD44+/CD24-/CK5/6+/ER- phenotype. Other analysed parameters were insignificant. We conclude that tumours with immunophenotypes: CD44+/CD24- and CD44+/CD24-/CK5/6+/ER- might be more sensitive for chemotherapy based on taxanes and/or anthracyclines.
    Journal of molecular histology 07/2013; DOI:10.1007/s10735-013-9523-6 · 1.98 Impact Factor
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    • "Aldehyde dehydrogenase 1 (ALDH1), identified as a breast CSC marker, has been associated with chemoresistance and poor prognosis (Pearce et al, 2005; Ginestier et al, 2007; Tanei et al, 2009). As ALDH1 was reportedly upregulated in triple-negative tumours and tumours arising in African women, which share several similarities with those arising from young women, we hypothesise that a relative abundance of ALDH1-positive CSCs may account for the poor outcome in younger women despite aggressive treatment (Ginestier et al, 2007; Nalwoga et al, 2010; Zhou et al, 2010; Ohi et al, 2011; Idowu et al, 2012). In this study, we used ALDH1 *Correspondence: Dr EY Tan; E-mail: or PH Tan; E-mail: tan.puay. "
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    ABSTRACT: Background: Tumours arising in younger women appear to be biologically more aggressive and tend to have a poorer outcome. Being relatively resistant to conventional treatments, breast cancer stem cells (CSCs) have been postulated as a possible cause of disease recurrence after treatment. In this study, we used ALDH1 as a CSC marker and determined whether ALDH1 expression correlated with clinical outcome in young women with breast cancer. Methods: The expression of ALDH1 was evaluated through immunohistochemistry on microarrayed cores obtained from 141 consecutive patients up to 35 years of age. Results: The expression of ALDH1 was observed in 25% (35 of 141) of tumours, in a median of 5% of cells. Younger women were 14 times more likely to have ALDH1-positive tumours (P<0.01, OR 14.4, 95% CI 4.34–48.09). The ALDH1 correlated independently with ER negativity (P=0.01, OR 0.33, 95% CI 0.15–0.77). There was no correlation with disease recurrence or breast cancer-related deaths. Conclusion: In younger women, ALDH1 was more highly expressed, and it correlated with ER negativity. It, however, did not predict survival in this study.
    British Journal of Cancer 06/2013; 109(1):109-113. DOI:10.1038/bjc.2013.297 · 4.82 Impact Factor
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