DAB2IP attenuates chemoresistance of triple-negative breast cancer through sequestration of RAC1 to prevent β-catenin nuclear accumulation

Background: Although chemotherapy, the most widely used systemic treatment in triple-negative breast cancer (TNBC), markedly improved the patients' outcome, chemoresistance always occurs. This study purposed to explore new therapeutic strategies for the treatment of chemoresistance.

Methods and results: The expression and prognostic value of DAB2IP were investigated in TNBC tissues and cell lines. Low DAB2IP expression predicted high mortality risk in TNBC. Inhibition of DAB2IP expression conferred cancer stem cell capacity and chemoresistance in TNBC cell lines. Using murine breast cancer (BC) xenograft models, we evaluated the association with DAB2IP and chemoresistance. DAB2IP inhibited TNBC tumourigenesis and chemoresistance in vivo. Further, we revealed that DAB2IP inhibited β-catenin nuclear transport through competitive interaction with RAC1 and decreased β-catenin accumulation in the cell nucleus. Finally, we found that the DNA methylation level was negatively associated with DAB2IP expression in TNBC. Inhibition of DNA methylation restored the DAB2IP expression and attenuated chemoresistance in TNBC.

Conclusions: We revealed that DAB2IP attenuates chemoresistance of TNBC via inhibition of RAC1-mediated β-catenin nuclear accumulation. Decitabine treatment results in re-expression of DAB2IP by inhibiting DNA methylation and could be a potential therapeutic strategy for chemoresistance in TNBC.