ABSTRACT
BACKGROUND: Colorectal cancers are often chemoresistant toward antitumour drugs that are substrates for ABCB1-mediated multidrug resistance (MDR). Activation of the Wnt/ß-catenin pathway is frequently observed in colorectal cancers. This study investigates the impact of activated, gain-of-function ß-catenin on the chemoresistant phenotype. METHODS: The effect of mutant (mut) ß-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 ß-catenin, and patients' tumours. Chemosensitivity towards 24 anticancer drugs was determined by high throughput screening. RESULTS: Cell lines with mut ß-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 ß-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 ß-catenin genotypes. CONCLUSION: Although ABCB1 is dominantly regulated by mut ß-catenin, this did not lead to drug resistance in the isogenic cell line model studied. In patient samples, the same ß-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.
