IRF-1 expression induces apoptosis and inhibits tumor growth in mouse mammary cancer cells in vitro and in vivo

• Published in: Oncogene Vol. 23; no. 5; pp. 1125 - 1135
• Main Authors: KIM, Peter K. M, ARMSTRONG, Michaele, YE LIU, PENG YAN, BUCHER, Brian, ZUCKERBRAUN, Brian S, GAMBOTTO, Andrea, BILLIAR, Timothy R, YIM, John H
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 05-02-2004; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Ageing, cell death; Animals; Apoptosis - genetics; Biological and medical sciences; Caspases - analysis; Cell Line; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Injections, Subcutaneous; Interferon Regulatory Factor-1; Mammary gland diseases; Mammary Glands, Animal; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Molecular and cellular biology; Phosphoproteins - genetics; Phosphoproteins - metabolism; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Proteins - analysis; Transplantation, Isogeneic; Tumors; interferon regulatory factor-1 (IRF-1); Enzyme; Rodentia; Caspase; Breast cancer; Malignant tumor; Gene expression; Carcinogenesis; In vitro; Mammary gland diseases; Peptidases; In vivo; Vertebrata; Mammalia; Mouse; Hydrolases; Interferon; Mammary gland; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207023

Interferon regulatory factor-1 (IRF-1) is a nuclear transcription factor that mediates interferon and other cytokine effects and appears to have antitumor activity in vitro and in vivo in cancer cells. We have constructed a recombinant adenoviral vector (Ad-IRF-1) that infects mammary cells with high efficiency and results in high levels of functional IRF-1 protein in transfected cells. Overexpression of IRF-1 in two mouse breast cancer cell lines, C3-L5 and TS/A, resulted in apoptosis in these cell lines as assessed by Annexin V staining. The involvement of caspases was confirmed by significant inhibition of apoptosis by a caspase inhibitor, and by demonstration of caspase-3 activity, cleavage of caspase-3, and PARP cleavage. Interestingly, the growth of nonmalignant breast cell lines C127I and NMuMG did not appear to be inhibited by IRF-1 overexpression. Suppression of growth for breast cancer cell lines in vivo was demonstrated by both preinfection of breast cancer cells ex vivo and by intratumoral injection of Ad-IRF-1 into established tumors in their natural hosts. The mechanism of apoptosis may involve the transcriptional upregulation of bak, caspase-8, and caspase-7 expression. These data support the antitumor potential of IRF-1 and the use of agents that increase IRF-1 in breast cancer.