Selectivity of a replication-competent adenovirus for human breast carcinoma cells expressing the MUC1 antigen

• Published in: The Journal of clinical investigation Vol. 106; no. 6; pp. 763 - 771
• Main Authors: Kurihara, T, Brough, D E, Kovesdi, I, Kufe, D W
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.09.2000
• Subjects: Adenoviridae - genetics; Adenovirus E1A Proteins - genetics; Adenovirus E1A Proteins - metabolism; Animals; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Breast Neoplasms - chemistry; Breast Neoplasms - genetics; Breast Neoplasms - therapy; Cell Division; Cytomegalovirus - genetics; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Genetic Therapy; Histocytochemistry; Humans; Mice; Mice, Nude; Mucin-1 - analysis; Mucin-1 - genetics; Neoplasm Transplantation; Promoter Regions, Genetic; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - therapeutic use; Virus Replication - genetics
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci9180

The DF3/MUC1 gene is aberrantly overexpressed in human breast and other carcinomas. Previous studies have demonstrated that the DF3/MUC1 promoter/enhancer confers selective expression of diverse transgenes in MUC1-positive breast cancer cells. In this study, we show that an adenoviral vector (Ad.DF3-E1) in which the DF3/MUC1 promoter drives expression of E1A selectively replicates in MUC1-positive breast cancer cells. We also show that Ad.DF3-E1 infection of human breast tumor xenografts in nude mice is associated with inhibition of tumor growth. In contrast to a replication-incompetent adenoviral vector that infects along the injection track, Ad.DF3-E1 infection was detectable throughout the tumor xenografts. To generate an Ad.DF3-E1 vector with the capacity for incorporating therapeutic products, we inserted the cytomegalovirus (CMV) promoter upstream of the TNF cDNA. Infection with Ad.DF3-E1/CMV-TNF was associated with selective replication and production of TNF in cells that express MUC1. Moreover, treatment of MUC1-positive, but not MUC1-negative, xenografts with a single injection of Ad.DF3-E1/CMV-TNF was effective in inducing stable tumor regression. These findings demonstrate that the DF3/MUC1 promoter confers competence for selective replication of Ad.DF3-E1 in MUC1-positive breast tumor cells, and that the antitumor activity of this vector is potentiated by integration of the TNF cDNA.