Ectopic Expression of Interferon Regulatory Factor-1 Promotes Human Breast Cancer Cell Death and Results in Reduced Expression of Survivin

Publisher Website
Google Scholar
Abstract
The overexpression of the inhibitor of apoptosis protein, survivin, may provide tumor cells with a distinct survival advantage in situ; hence, therapeutic strategies have been designed to inhibit its expression. In this study, we ectopically expressed the interferon regulatory factor (IRF)-1 protein in the breast carcinoma cell lines MDA-MB-468 and SK-BR-3 using a recombinant adenovirus (Ad-IRF-1). By screening microarray analysis of cDNA from the human breast cancer cell line MDA-MB-468 infected with Ad-IRF-1, we observed a 15-fold down-regulation of the survivin gene when compared with uninfected cells. Consequently, we tested survivin expression in Ad-IRF-1-infected MDA-MB-468 and SK-BR-3 breast cancer cell lines. Immunoblotting analyses supported the contention that ectopic expression of the IRF-1 protein results in down-regulation of survivin protein expression that is independent of p53. In addition, Ad-IRF-1 infection of these human breast cancer cell lines induces the expression of p21. We also report that increased apoptosis is observed in tumor cells infected with Ad-IRF-1 compared with Ad-Ψ5 mock-infected cells and that cell death is further augmented when the IRF-1-infected cells are cultured with Adriamycin. Moreover, in a xenogeneic mouse model of breast carcinoma, in vivo treatment of tumor-bearing mice with intratumoral Ad-IRF-1 injections results in tumor growth inhibition. In resected tumors from mice that had been treated with Ad-IRF-1, tumor cells that express the IRF-1 transgene have a predominant IRF-1-positive, survivin-negative phenotype. Collectively, these observations suggest that therapies designed to enhance IRF-1 expression within tumor cells may represent novel treatment strategies for breast cancer.