Abstract A16: Requirement of functionally active BRCA2 protein for the expression of IRF9-regulated genes in human breast cells

Abstract

Abstract Interferons are cytokines that induces antiviral, immunomodulatory and antiproliferative effects to cells by inducing the expressions of many effector proteins. Type I interferons are often used to treat advanced stages of breast cancer. Unfortunately, in many cases interferon treatment does not produce any significant effect. We found that transient ablation of the breast cancer susceptibility gene BRCA2 in the human breast cells impairs the expressions of many type I interferon regulated genes. Thus, it appears that type I interferons need functional BRCA2 for their actions. We tested the promoter activity of several of the interferon target genes, such as GBP1, GBP2, ISG15, MX1, MX2, PKR etc. in the BRCA2 knocked-down human breast cells with or without added INF-alpha2a. The interferon-stimulated activity of the promoter decreased significantly in the BRCA2 knocked-down cells, further suggesting a possible role of BRCA2 in the interferon signal transduction pathway. Over expression of BRCA2 in the BRCA2-deficient pancreatic cancer cell Capan1 significantly increased the interferon-stimulated activity of the IFN-alpha-regulated gene promoters in these cells. We tested whether BRCA2 helps mediating the interferon pathway by interacting with the components of this pathway. The classical signal transduction pathway for the type I interferons involve the formation of the ternary complex ISGF3 among phosphorylated STAT1 and STAT2 with IRF9. Immuno-pull-down experiments revealed the binding of STAT1, STAT2 and IRF9 with BRCA2 in the human breast cells. Our study thus proposes a not-known-before role of the breast cancer susceptibility protein BRCA2 in the type I interferon pathway. Supported by the generous funding from US Department of Defense IDEA grant #W81XWH-08-1-0446 to GC. Citation Information: Cancer Res 2009;69(23 Suppl):A16.