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.
[Show abstract][Hide abstract] ABSTRACT: Purpose
Breast cancer displays varying molecular and clinical features. The ability to form breast tumors has been shown by several studies with aldehyde dehydrogenase 1 (ALDH1) positive cells. The aim of this study is to investigate the association between ALDH1 expression and clinicopathologic characteristics of invasive ductal carcinoma.
We investigated breast cancer tissues for the prevalence of ALDH1+ tumor cells and their prognostic value. The present study included paraffin-embedded tissues of 70 patients with or without recurrences. We applied immunohistochemical staining for the detection of ALDH1+ cells. Analysis of the association of clinical outcomes and molecular subtype with marker status was conducted.
ALDH1+ and ALDH1- tumors were more frequent in triple-negative breast cancers and in luminal A breast cancers, respectively (p<0.01). ALDH1 expression was found to exert significant impact on disease free survival (DFS) (ALDH1+ vs. ALDH1-, 53.1±6.7 months vs. 79.2±4.7 months; p=0.03) and overall survival (OS) (ALDH1+ vs. ALDH1-, 68.5±4.7 months vs. 95.3±1.1 months; p<0.01). In triple-negative breast cancer (TNBC) patients, DFS and OS showed no statistical differences according to ALDH1 expression (ALDH1+ vs. ALDH1-, 45.3±9.4 months vs. 81.3±7.4 months, p=0.52; 69.0±7.5 months vs. 91.3±6.3 months, p=0.67). However, non-TNBC patients showed significant OS difference between ALDH1+ and ALDH1- tumors (ALDH1+ vs. ALDH1-, 77.6±3.6 months vs. 98.0±1.0 months; p=0.04) with no statistical difference of DFS (ALDH1+ vs. ALDH1-, 60.5±8.0 months vs. 81.8±4.6 months; p=0.27).
Our findings suggest that the expression of ALDH1 in breast cancer may be associated with TNBC and poor clinical outcomes. On the basis of our findings, we propose that ALDH1 expression in breast cancer could be correlated with poor prognosis, and may contribute to a more aggressive cancer phenotype.
Journal of Breast Cancer 06/2014; 17(2):121-8. DOI:10.4048/jbc.2014.17.2.121 · 1.58 Impact Factor
"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. "
[Show abstract][Hide abstract] 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.
"Furthermore, breast CSCs can be isolated based on expression of CD44(+)/CD24(-/low), and aldehyde dehydrogenase activity (ALDH1+) [22,23]. Noteably, CD44(+)/CD24(-/low) breast cancer stem-like cells are associated with tumor recurrence  and play a pivotal role in the clinical behavior of triple-negative breast cancer, a particularly therapy-resistant subclass of breast cancer . Therefore, the development of therapies eliminating CD44(+)/CD24(-/low) CSCs or impeding activation of the signaling pathways these cells rely on may represent a promising approach for basal-like breast cancer. "
[Show abstract][Hide abstract] ABSTRACT: Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a coreceptor for growth factors and chemokines and is a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of Syndecan-1-deficient mice to experimentally-induced tumorigenesis has been linked to altered Wnt-responsive precursor cell pools, suggesting a potential role of Syndecan-1 in breast cancer cell stem function. However, the precise molecular mechanism is still elusive. Here, we decipher the functional impact of Syndecan-1 knockdown using RNA interference on the breast cancer stem cell phenotype of human triple-negative MDA-MB-231 and hormone receptor-positive MCF-7 cells in vitro employing an analytical flow cytometric approach. Successful Syndecan-1 siRNA knockdown was confirmed by flow cytometry. Side population measurement by Hoechst dye exclusion and Aldehyde dehydrogenase-1 activity revealed that Syndecan-1 knockdown in MDA-MB-231 cells significantly reduced putative cancer stem cell pools by 60% and 27%, respectively, compared to controls. In MCF-7 cells, Syndecan-1 depletion reduced the side population by 40% and Aldehyde dehydrogenase-1 by 50%, repectively. In MDA-MB-231 cells, the CD44(+)CD24(-/low) phenotype decreased significantly by 6% upon siRNA-mediated Syndecan-1 depletion. Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated by >40% in Syndecan-1-silenced MDA-MB-231 cells, which showed a dysregulated response to IL-6-induced shifts in E-cadherin and vimentin expression. Furthermore, activation of STAT-3 and NFkB transcription factors and expression of a coreceptor for Wnt signaling, LRP-6, were reduced by >45% in Syndecan-1-depleted cells compared to controls. At the functional level, Syndecan-1 siRNA reduced the formation of spheres and cysts in MCF-7 cells grown in suspension culture. Our study demonstrates the viability of flow cytometric approaches in analyzing cancer stem cell function. As Syndecan-1 modulates the cancer stem cell phenotype via regulation of the Wnt and IL-6/STAT3 signaling pathways, it emerges as a promising novel target for therapeutic approaches.
PLoS ONE 12/2013; 8(12):e85737. DOI:10.1371/journal.pone.0085737 · 3.23 Impact Factor
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