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| Item Type: | Article |
|---|---|
| Title: | Impact of mutant beta-catenin on ABCB1 expression and therapy response in colon cancer cells |
| Creators Name: | Stein, U., Fleuter, C., Siegel, F., Smith, J., Kopacek, A., Scudiero, D.A., Hite, K.M., Schlag, P.M., Shoemaker, R.H. and Walther, W. |
| Abstract: | Background: Colorectal cancers are often chemoresistant toward antitumour drugs that are substrates for ABCB1-mediated multidrug resistance (MDR). Activation of the Wnt/beta-catenin pathway is frequently observed in colorectal cancers. This study investigates the impact of activated, gain-of-function beta-catenin on the chemoresistant phenotype. Methods: The effect of mutant (mut) beta-catenin on ABCB1 expression and promoter activity was examined using HCT116 human colon cancer cells and isogenic sublines harbouring gain-of-function or wild-type beta-catenin, and patients' tumours. Chemosensitivity towards 24 anticancer drugs was determined by high throughput screening. Results: Cell lines with mut beta-catenin showed high ABCB1 promoter activity and expression. Transfection and siRNA studies demonstrated a dominant role for the mutant allele in activating ABCB1 expression. Patients' primary colon cancer tumours shown to express the same mut beta-catenin allele also expressed high ABCB1 levels. However, cell line chemosensitivities towards 24 MDR-related and non-related antitumour drugs did not differ despite different beta-catenin genotypes. Conclusion: Although ABCB1 is dominantly regulated by mut beta-catenin, this did not lead to drug resistance in the isogenic cell line model studied. In patient samples, the same beta-catenin mutation was detected. The functional significance of the mutation for predicting patients' therapy response or for individualisation of chemotherapy regimens remains to be established. |
| Keywords: | Colon Cancer, Beta-Catenin, Multidrug Resistance, ABCB1, Therapy Response |
| Source: | British Journal of Cancer |
| ISSN: | 0007-0920 |
| Publisher: | Nature Publishing Group |
| Volume: | 106 |
| Number: | 8 |
| Page Range: | 1395-1405 |
| Date: | 10 April 2012 |
| Official Publication: | https://doi.org/10.1038/bjc.2012.81 |
| PubMed: | View item in PubMed |
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