β-Glucosidase inhibition sensitizes breast cancer to chemotherapy.

The resistance to therapy is a major clinical challenge for advanced stage breast cancer. Identification of novel potential therapeutic targets is needed to overcome chemoresistance. In this work, we identified a target that was critically involved in breast cancer growth and chemoresistance. We demonstrated that β-glucosidase expression and activity were significantly upregulated in breast cancer tissues and a panel of cell lines compared to normal adjacent breast tissues and cell lines. β-glucosidase overexpression activated PI3K/Akt/mTOR signalling, leading to increased cell growth. In contrast, β-glucosidase inhibition by siRNA depletion and pharmacological approach using conduritol B epoxide (selective β-glucosidase inhibitor) suppressed growth and induced apoptosis in breast cancer cells. Importantly, β-glucosidase inhibition significantly sensitized breast cancer cells to chemotherapy in vitro and in vivo, suggesting that inhibiting β-glucosidase effectively targeted breast cancer cells that were resistant to elimination by chemotherapeutic agent alone. We demonstrated the positive role of β-glucosidase in breast cancer growth and survival. Our work also suggested that inhibiting β-glucosidase as a possible alternative therapeutic strategy to overcome chemoresistance in breast cancer.