ABSTRACT
Epidemiological and molecular evidence links Epstein-Barr virus (EBV) carriage to the pathogenesis of human malignancies of lymphoid and epithelial cell origin but the mechanisms of viral oncogenesis are poorly understood. Burkitt's lymphoma, a tumor occurring in both EBV-positive and -negative forms, provides a convenient model for analysis of the relative contribution of genetic changes and viral products that are expressed in the malignant cells. Here we review recent findings that highlight several mechanisms by which EBV could play an important role in oncogenesis by promoting genomic instability.
Subject(s)
Burkitt Lymphoma/virology , Epstein-Barr Virus Infections/virology , Genomic Instability , Herpesvirus 4, Human/physiology , Animals , HumansABSTRACT
The Epstein-Barr virus (EBV) nuclear antigen (EBNA)-1 is the only viral protein expressed in all EBV-carrying malignancies, but its contribution to oncogenesis has remained enigmatic. We show that EBNA-1 induces chromosomal aberrations, DNA double-strand breaks, and engagement of the DNA damage response (DDR). These signs of genomic instability are associated with the production of reactive oxygen species (ROS) and are reversed by antioxidants. The catalytic subunit of the leukocyte NADPH oxidase, NOX2/gp91(phox), is transcriptionally activated in EBNA-1-expressing cells, whereas inactivation of the enzyme by chemical inhibitors or RNAi halts ROS production and DDR. These findings highlight a novel function of EBNA-1 and a possible mechanism by which expression of this viral protein could contribute to malignant transformation and tumor progression.
Subject(s)
Epstein-Barr Virus Nuclear Antigens/metabolism , Reactive Oxygen Species , Antigens, Viral/chemistry , Antioxidants , Catalytic Domain , Cell Transformation, Neoplastic , DNA Damage , Disease Progression , Genomic Instability , Humans , Membrane Glycoproteins/metabolism , Models, Biological , NADP/chemistry , NADPH Oxidase 2 , NADPH Oxidases/metabolism , Neoplasms/pathology , Transcriptional ActivationABSTRACT
BACKGROUND: Cyclin E is a cell cycle regulatory protein which occurs in G1, peaks in late G1 and is degraded in early S-phase. Cyclin E overexpression appears to be an independent prognostic factor for overall survival in breast cancer. Nuclear cyclin A is a reliable marker for S-and G2-phases. Consequently, aberrant expression of cyclin E can be detected by simultaneous immunostainings for cyclin A and cyclin E. Studies have shown that aberrant cyclin E might provide additional prognostic information compared to that of cyclin E alone. This study aimed to investigate cyclin E and aberrant cyclin E expression in low-risk node negative breast cancer. MATERIAL AND METHODS: We compared women that died from their breast cancer (n=17) with women free from relapse > 8 years after initial diagnosis (n=24). All women had stage I, low risk breast cancer. The groups were matched regarding tumour size, receptor status, adjuvant chemotherapy and tumour differentiation. Tumour samples were analysed regarding expression of cyclin A, cyclin E and double-stained tumour cells using immunoflourescence staining and digital microscopy. RESULTS: No differences were seen regarding expression of cyclin E or aberrant cyclin E in cases compared to controls. DISCUSSION: We conclude that neither cyclin E nor aberrant cyclin E is a prognostic factor in low-risk node negative breast cancer patients.
