| Popis: |
Wnt signalling components are reported to be deregulated in breast cancer but the contribution of this pathway in endocrine resistance is less clearly defined. Endocrine resistance is an important clinical challenge affecting up to a quarter of all breast cancer patients and is associated with a poorer clinical prognosis. This project focussed on exploring the role of Wnt signalling in endocrine resistant breast cancer cell models. Wnt pathway elements were deregulated in the acquired tamoxifen resistant cell line (Tam-R) compared to tamoxifen sensitive parental cells (MCF-7), with changes supportive of Wnt signalling activation in this tamoxifen resistant model apparent from Affymetrix HGU-133A gene microarray data and Western blot analysis. In contrast, Wnt signalling appeared to be suppressed based on Affymetrix data for MCF-7 cells treated with oestradiol for 10 days, with equivocal changes in MCF-7 cells treated with tamoxifen for 10 days or a faslodex resistant cell model (Fas-R). Excitingly, Tam-R cells were also more sensitive than MCF-7 cells to pharmacological manipulation of Wnt signalling. While Wnt activation using Wnt3a and LiCl did not affect cell growth or migration, inhibition of Wnt signalling usingIWP2, PNU 74654 and iCRT14 suppressed Tam-R cell growth and migration. There is mounting evidence of cross talk between Wnt and EGFR signalling in breast cancer, and EGFR activity is upregulated in Tam-R cells. The project’s findings tentatively supported cross-talk between the two signalling pathways in this model. Thus, targeting of the Wnt pathway alongside EGFR blockade was superior in suppressing cell growth and migration in Tam-R cells. The effect appeared to be more pronounced when Wnt signalling was inhibited at the nuclear level using iCRT14. Collectively, these data suggest that Wnt signalling may play an important role in tamoxifen resistance where it may offer an opportunity for more effective therapeutic intervention to control relapse and associated tumour aggressiveness. |
