Y-Box Binding Protein-1 Induces the Expression of CD44 and CD49f Leading to Enhanced Self-Renewal, Mammosphere Growth, and Drug Resistance
| Autor: | Jing Wang, Connie J. Eaves, Lawrence K. Lee, Jennifer Law, Kristen Reipas, Sandra E. Dunn, Pauline Johnson, Anna L. Stratford, Isabelle M. Berquin, Afshin Raouf, Karen To, Alastair H. Davies, Abbas Fotovati, Hans-Dieter Royer, Arezoo Astanehe, Kaiji Hu |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Paclitaxel Breast Neoplasms Mice Transgenic Cell Growth Processes Integrin alpha6 Biology Mice Cancer stem cell Cell Line Tumor Animals Humans Gene silencing Translation factor Regulation of gene expression CD44 Nuclear Proteins Y box binding protein 1 Antineoplastic Agents Phytogenic Molecular biology DNA-Binding Proteins Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Hyaluronan Receptors Oncology Drug Resistance Neoplasm Cell culture Cancer cell biology.protein Cancer research Female Y-Box-Binding Protein 1 |
| Zdroj: | Cancer Research. 70:2840-2851 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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-1S102 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-1S102D 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-1S102 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 CD44High/CD24Low cells to paclitaxel. In conclusion, YB-1 promotes cancer cell growth and drug resistance through its induction of CD44 and CD49f. Cancer Res; 70(7); 2840–51 |
| Databáze: | OpenAIRE |
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