The Wnt signaling pathway plays a key role in embryonic development and defects in this pathway have also been implicated in the carcinogenesis of various types of tumors. Constitutive activation of beta-catenin and increased expression of specific Wnt target genes have been found frequently in breast cancer. The aim of the study was to investigate whether targeting the Wnt signaling suppresses growth of breast cancer cells and/or sensitizes them to irradiation through induction of apoptosis.

The expression of the Wnt antagonists Dickkopf gene family (Dkk1-4) in breast cancer cells was analysed using Real-Time PCR and Immunohistochemistry. The breast carcinoma cell lines with activated transcriptional beta-catenin were engineered to express high levels of either Dkk-1 or Siah1 protein by stable transfection. Cells were irradiated with different doses and apoptosis was assessed using FACS based ssay.

Reduction and/or loss of expression of the Wnt antagonists dickkopf gene family (Dkk1-4) was frequently found in breast cancer cells. Overexpression of Dkk1 in breast cancer cells with an elevated transcriptional activity of beta-catenin inhibited cell growth and enhanced radiation- induced apoptosis in a dose- dependent manner. Similarly, degradation of beta-catenin by enhanced expression of the ubiquitin ligase Siah1 further potentiated the apoptotic effect of irradiation. Our data suggest potential clinical application of targeting the Wnt signaling for treatment of breast cancer. Selective interruption of Wnt signalling pathway within tumour might provide a useful therapeutic strategy.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA