Hyper-dependence of breast cancer cell types on the nuclear transporter Importin β1

We previously reported that overexpression of members of the Importin (Imp) superfamily of nuclear transporters results in increased nuclear trafficking through conventional transport pathways in tumour cells. Here we show for the first time that the extent of overexpression of Imp beta 1 correlates with disease state in the MCF10 human breast tumour progression system. Excitingly, we find that targeting Imp beta 1 activity through siRNA is >30 times more efficient in decreasing the viability of malignant ductal carcinoma cells compared to isogenic non-transformed counterparts, and is highly potent and tumour selective at subnanomolar concentrations. Tumour cell selectivity of the siRNA effects was unique to Imp beta 1 and not other Imps, with flow cytometric analysis showing >60% increased cell death compared to controls concomitant with reduced nuclear import efficiency as indicated by confocal microscopic analysis. This hypersensitivity of malignant cell types to Imp beta 1 knockdown raises the exciting possibility of anti-cancer therapies targeted at Imp beta 1. (C) 2015 Elsevier B.V. All rights reserved.