title: Hyper-dependence of breast cancer cell types on the nuclear transporter Importin β1.
abstract: 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 Impβ1 correlates with disease state in the MCF10 human breast tumour progression system. Excitingly, we find that targeting Impβ1 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 Impβ1 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 Impβ1 knockdown raises the exciting possibility of anti-cancer therapies targeted at Impβ1.
authors.affiliation: Nuclear Signalling Laboratory, Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, Australia; ARC Centre of Excellence for Biotechnology and Development, Australia.
authors.forename: Henna V
authors.initials: HV
authors.lastname: Kuusisto
authors.affiliation: Nuclear Signalling Laboratory, Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, Australia; ARC Centre of Excellence for Biotechnology and Development, Australia. Electronic address: David.Jans@monash.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Jans
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000494:pharmacology; D028961:beta Karyopherins / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C424166:KPNB1 protein, human; D034741:RNA, Small Interfering; D028961:beta Karyopherins
keywords: Importin; Isogenic cell pairs; Silencing RNA; Transformed cells