NF-κB, stem cells and breast cancer: The links get stronger

Interdisciplinary Cluster for Applied Genoproteomics (GIGA-Research), Unit of Medical Chemistry and GIGA-Signal Transduction, University of Liege, CHU, Sart-Tilman, 4000 Liège, Belgium.
Breast cancer research: BCR (Impact Factor: 5.49). 07/2011; 13(4):214. DOI: 10.1186/bcr2886
Source: PubMed


Self-renewing breast cancer stem cells are key actors in perpetuating tumour existence and in treatment resistance and relapse. The molecular pathways required for their maintenance are starting to be elucidated. Among them is the transcription factor NF-κB, which is known to play critical roles in cell survival, inflammation and immunity. Recent studies indicate that mammary epithelial NF-κB regulates the self-renewal of breast cancer stem cells in a model of Her2-dependent tumourigenesis. We will describe here the NF-κB-activating pathways that are involved in this process and in which progenitor cells this transcription factor is actually activated.

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    • "Clearly, the NCAM1 expression domain exceeds that of the WT CSC. In this regard, our genomic and proteomic data disclose several specific pathways (e.g., NF-kB, Wnt, PI3K, and mTOR) previously implicated in stemness acquisition (Armstrong et al., 2006; Huang et al., 2012; Katoh and Katoh, 2007; Shostak and Chariot, 2011) as highly operative in WT CSCs. Thus, global analysis not only sheds light on the WT CSC as possessing enhanced stemness alongside a more differentiated renal phenotype but also pinpoints interventions such as mTOR and epidermal growth factor receptor inhibition that may prove beneficial in WT CSC eradication. "
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    ABSTRACT: An open question remains in cancer stem cell (CSC) biology whether CSCs are by definition at the top of the differentiation hierarchy of the tumor. Wilms' tumor (WT), composed of blastema and differentiated renal elements resembling the nephrogenic zone of the developing kidney, is a valuable model for studying this question because early kidney differentiation is well characterized. WT neural cell adhesion molecule 1-positive (NCAM1(+)) aldehyde dehydrogenase 1-positive (ALDH1(+)) CSCs have been recently isolated and shown to harbor early renal progenitor traits. Herein, by generating pure blastema WT xenografts, composed solely of cells expressing the renal developmental markers SIX2 and NCAM1, we surprisingly show that sorted ALDH1(+) WT CSCs do not correspond to earliest renal stem cells. Rather, gene expression and proteomic comparative analyses disclose a cell type skewed more toward epithelial differentiation than the bulk of the blastema. Thus, WT CSCs are likely to dedifferentiate to propagate WT blastema.
    Stem Cell Reports 07/2014; 3(1). DOI:10.1016/j.stemcr.2014.05.013 · 5.37 Impact Factor
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    • "NF-κB jest czynnikiem transkrypcyjnym biorącym udział między innymi w kontrolowaniu proliferacji i żywotności komórki [32]. Samoodnawiające się macierzyste komórki raka piersi są przyczyną istnienia nowotworu, a także pełnią główną rolę w przypadku nawrotu choroby i oporności na terapię lekową [71]. Najnowsze badania sugerują, że NFκB komórek nabłonkowych gruczołu sutkowego reguluje samoodnowę w linii komórkowej zależnej od drugiego receptora ludzkiego czynnika wzrostu nabłonka -HER-2 [49]. "
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    ABSTRACT: Breast cancer is the most common malignant cancer among women, both in Poland and worldwide. Due to the constantly increasing number of breast cancer cases, it is vital to develop effective activities in primary and secondary prevention. One of the promising methods of best value, connecting both types of cancer prevention, appears to be chemoprevention. Chemoprevention uses natural or synthetic compounds to inhibit, delay or reverse the process of carcinogenesis. Among ingredients of natural origin, great attention is paid to curcumin - a broad-spectrum anti-cancer polyphenol derivative, extracted from the rhizome of Curcuma longa L. Curcumin has a number of chemopreventive properties such as anti-inflammatory activity, induction of apoptosis, inhibition of angiogenesis as well as tumor metastasis. Numerous in vitro and in vivo studies have demonstrated the mentioned anti-cancer effect in the epithelial breast cell line MCF-10A and in the epithelial breast cell lines MCF-7, BT-474, SK-BR-3-hr and MDA-MB-231. The main problem associated with the use of curcumin as a chemopreventive agent in humans is its low absorption from the gastrointestinal tract, poor solubility in body fluids and low bioavailability. Current studies are underway to increase the bioavailability and effectiveness of curcumin in vivo. Good results in the prevention and the treatment of breast cancer could be ensured by curcumin nanoparticles coated with albumin, known as nanocurcumin. The studies using nanocurcumin, however, are still in the preclinical stage, which is why there is a need to conduct extensive long-term randomized clinical trials to determine its effectiveness.
    Postępy Higieny i Medycyny Doświadczalnej (Advances in Hygiene and Experimental Medicine) 01/2014; 68:571-8. DOI:10.5604/17322693.1102294 · 0.57 Impact Factor
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    • "Transcription factors found constitutively activated in CSCs include STAT3 and NF-kB [5], [6]. Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor that conveys various signals of cytokines and growth factors from the cell membrane to nucleus [7]. "
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    ABSTRACT: Mounting clinical data suggest that high telomerase activity is tightly associated with cancer progression and poor outcomes. Constitutively activated STAT3 is found in ∼60% of human malignancies and shows a dismal prognosis. We previously reported that activated STAT3 promoted epithelial-mesenchymal transition (EMT) and cancer stem cell phenotype in human breast cancer. However, little is known how STAT3 is regulated in the cancer stem cell and by which mechanisms STAT3 contributes to poor prognosis in aggressive breast cancer. Here we demonstrate that STAT3 physically interacts with CD44 and NF-kB and activates the catalytic subunit of telomerase (hTERT) in human breast cancer stem cells. STAT3 plays a role as a signal transducing molecule between CD44 and NF-kB. In addition to functioning as a catalytic subunit of telomerase, hTERT has been reported to function as a transcription co-factor which drives EMT and cancer stem cell phenotype in human cancer. We observed that activated hTERT increases CD44 (+) subpopulation, whereas targeted knock-down of hTERT abolished cancer stem cell phenotype. Targeted STAT3 knock-down cells also down-regulated hTERT and decreased CD44 subpopulation. Finally, CD44 knock-down resulted in the abrogation of cancer stem cell phenotype and concurrent down-regulation of pSTAT3 and hTERT. Our study delineates the signaling pathway where STAT3 functions as a modulator for CD44 and hTERT, promoting a cancer stem cell phenotype. The constitutive activation of STAT3 signaling that leads to regulation of hTERT pathway may provide novel therapeutic targets for human breast cancer stem cells.
    PLoS ONE 12/2013; 8(12):e83971. DOI:10.1371/journal.pone.0083971 · 3.23 Impact Factor
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