Y-Box Binding Protein-1 Induces the Expression of CD44 and CD49f Leading to Enhanced Self-Renewal, Mammosphere Growth, and Drug Resistance

Experimental Medicine Program, University of British Columbia, Canada.
Cancer Research (Impact Factor: 9.28). 03/2010; 70(7):2840-51. DOI: 10.1158/0008-5472.CAN-09-3155
Source: PubMed

ABSTRACT Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in >40% of breast cancers, where it is associated with poor prognosis, disease recurrence, and drug resistance. We questioned whether this may be linked to the ability of YB-1 to induce the expression of genes linked to cancer stem cells such as CD44 and CD49f. Herein, we report that YB-1 binds the CD44 and CD49f promoters to transcriptionally upregulate their expressions. The introduction of wild-type (WT) YB-1 or activated P-YB-1(S102) stimulated the production of CD44 and CD49f in MDA-MB-231 and SUM 149 breast cancer cell lines. YB-1-transfected cells also bound to the CD44 ligand hyaluronan more than the control cells. Similarly, YB-1 was induced in immortalized breast epithelial cells and upregulated CD44. Conversely, silencing YB-1 decreased CD44 expression as well as reporter activity in SUM 149 cells. In mice, expression of YB-1 in the mammary gland induces CD44 and CD49f with associated hyperplasia. Further, activated mutant YB-1(S102D) enhances self-renewal, primary and secondary mammosphere growth, and soft-agar colony growth, which were reversible via loss of CD44 or CD49f. We next addressed the consequence of this system on therapeutic responsiveness. Here, we show that paclitaxel induces P-YB-1(S102) expression, nuclear localization of activated YB-1, and CD44 expression. The overexpression of WT YB-1 promotes mammosphere growth in the presence of paclitaxel. Importantly, targeting YB-1 sensitized the CD44(High)/CD24(Low) cells to paclitaxel. In conclusion, YB-1 promotes cancer cell growth and drug resistance through its induction of CD44 and CD49f.

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Available from: Hans-Dieter Royer, Aug 20, 2015
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    • "This finding was confirmed by the clearance of Notch1 NICD immunostaining from the nuclei of T315-treated MDA-MB-231 cells (Figure 2B), as well as the dose-dependent suppressive effect of T315 on Notch reporter activity (Figure 2C) and the expression of various Notch downstream targets (Figure 2D), including HES1 [24],c-Myc[25],Nestin[26],and ABCG2 [27], in both MDA-MB-231 and SUM-159 cells. It is noteworthy that T315-mediated down-regulation of these Notch targets was accompanied by parallel decreases in the expression of CSCassociated epithelial-mesenchymal transition regulators, including zinc finger E-box binding homeobox 1 (ZEB1) [28], Twist [29],a n dY box-binding protein 1 [30], which were also reported to be downstream effectors of ILK [13] [31] (Figure 2D). Moreover, T315 was equipotent in downregulating other CSC-associated markers, including the Wnt signaling effector β-catenin and the hedgehog signaling effector Bmi1 (Figure 2D). "
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    Neoplasia (New York, N.Y.) 06/2015; 105(6). DOI:10.1016/j.neo.2015.06.001 · 5.40 Impact Factor
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    • "When this is done in conjunction with the classical histological grading system it could allow personalised treatment of high-risk groups of HNSCC patients. Taken into account that YB-1 expression is linked to multi drug resistance in various tumour entities so far as well as against EGFRtailored drugs (Kashihara et al, 2009) YB-1 expression was also found to be also involved in cancer stem cell biology (To et al, 2010) and trastuzumab resistance (Dhillon et al, 2010). In light of these findings and our recent observations that YB-1-based virotherapy kills cancer stem cells equipped with nuclear YB-1 expression (Mantwill et al, 2011; manuscript submitted to Stem Cells), we suggest that YB-1 analysis in conjunction with YB-1 based virotherapy represents an attractive therapeutic strategy for a multimodal treatment concept for high-risk subgroup of HNSCC patients. "
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    British Journal of Cancer 11/2011; 105(12):1864-73. DOI:10.1038/bjc.2011.491 · 4.82 Impact Factor
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    • "Although YB-1 upregulation is well characterized in breast cancer cell lines and advanced stage primary tumours (Habibi et al., 2008; Janz et al., 2002; Kohno et al., 2003; To et al., 2010), a role for the gene in tumour initiation and premalignant progression is unknown. Chromosomal aberrations observed in YB-1 transgenic mice prompted us to address if ectopic YB-1 expression in genetically stable HMECs acted to directly destabilize the genome as a prelude to malignancy (Bergmann et al., 2005). "
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