Mutant Bik expression mediated by the enhanced minimal topoisomerase IIalpha promoter selectively suppressed breast tumors in an animal model.
To ensure the success of systemic gene therapy, it is critical to enhance the tumor specificity and activity of the promoter. In the current study, we determined that topoisomerase IIalpha promoter is selectively activated in breast cancer cells. An element containing an inverted CCAAT box (ICB) was shown to be responsible for the breast cancer specificity. When the ICB-harboring topoisomerase IIalpha minimal promoter was linked with an enhancer sequence from the cytomegalovirus immediate early gene promoter (CMV promoter), this composite promoter, CT90, exhibited activity comparable to or higher than the CMV promoter in breast cancer cells in vitro and in vivo, yet expresses much lower activity in normal cell lines and normal organs than the CMV promoter. A CT90-driven construct expressing BikDD, a potent proapoptotic gene, was shown to selectively kill breast cancer cells in vitro, and to suppress mammary tumor development in an animal model of intravenously administrated, liposome-delivered gene therapy. Expression of BikDD was readily detectable in the tumors but not in the normal organs (such as heart) of CT90-BikDD-treated animals. The results indicate that liposomal CT90-BikDD is an effective systemic breast cancer-targeting gene therapy.
Day
C-P
CP
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Rau
K-M
KM
Qiu
L
L
Liu
C-W
CW
Kuo
H-P
HP
Xie
X
X
Lopez-Berestein
G
G
Hortobagyi
G N
GN
Hung
M-C
MC
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008081:Liposomes; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D024101:Mitochondrial Proteins; D009154:Mutation; D009374:Neoplasms, Experimental; D020218:Response Elements / Q000235:genetics*
D000951:Antigens, Neoplasm; D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D004268:DNA-Binding Proteins; D008081:Liposomes; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D004250:DNA Topoisomerases, Type II