Possible role of EBV in breast cancer and other unusually EBV-associated cancers

Hippocrate, Aurélie; Oussaief, Lassad; Joab, Irène

doi:10.1016/j.canlet.2010.11.007

Cited by 36 publications

(29 citation statements)

References 48 publications

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“…Similar suggestion has also been reported [10,28]. It should be also noted that finding the definite relationship between EBV and breast cancer in Iranian patients needs further studies on an increased number of patients.…”

Section: Discussionsupporting

confidence: 58%

Epstein-barr virus may not be associated with breast cancer in Iranian patients

Fadavi¹,

Rostamian²,

Arashkia³

et al. 2013

Oncol Discov

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Background: Epstein-Barr Virus (EBV) is a human herpes virus which infects over 90% of the world's population. This virus has been implicated in the pathogenesis of many types of cancers. Breast cancer is the most common cancer among women worldwide. EBV has been studied as a possible cause of human breast cancer. The data related to the possible association of EBV with breast cancer are contradictory and therefore inconclusive. Here we searched for EBV in Iranian patients with breast cancer. Methods: Paraffin embedded formalin fixed specimens were prepared from malignant tumor tissue from eighteen Iranian patients with clinically proven breast cancer. EBV as well as human cells were detected and quantified by PCR and real-time PCR, respectively. The ratio of EBV/human cells was calculated in specimens from all patients. Results: EBV was not detected in any of breast cancer tissues in our study. Quantitative analysis showed that EBV is not present in any specimens at level of one virus per each human cell. Conclusion: Our results showed that EBV may not be associated with breast cancer in our patients suggesting that EBV might not have a significant role in this disease in Iran.

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Section: Discussionsupporting

confidence: 58%

Epstein-barr virus may not be associated with breast cancer in Iranian patients

Fadavi¹,

Rostamian²,

Arashkia³

et al. 2013

Oncol Discov

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“…A link between the EBV and BC was first proposed when two studies detected EBV DNA in whole tumor material in 50% of their studied cases [7]. Following this report, other authors detected EBER-2 and LMP-2 DNA by polymerase chain reaction (PCR) in 51% of breast cancers, compared to only 10% in normal tissue from the same patients, thus demonstrating that the EBV could be restricted to tumor epithelial cells [8, 23]. In their study combining laser capture microdissection techniques with real-time quantitative PCR, Arbach et al detected EBV genomes in approximately 50% of BC specimens [4], revealing viral loads which greatly varied from tumor to tumor.…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr virus infection and clinical outcome in breast cancer patients correlate with immune cell TNF-α/IFN-γ response

Marrão

Habib

Paiva³

et al. 2014

BMC Cancer

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BackgroundFor nearly two decades now, various studies have reported detecting the Epstein-Barr virus (EBV) in breast cancer (BC) cases. Yet the results are unconvincing, and their interpretation has remained a matter of debate. We have now presented prospective data on the effect of EBV infection combined with survival in patients enrolled in a prospective study.MethodsWe assessed 85 BC patients over an 87-month follow-up period to determine whether EBV infection, evaluated by qPCR in both peripheral blood mononuclear cells (PBMCs) and tumor biopsies, interacted with host cell components that modulate the evolution parameters of BC. We also examined the EBV replicating form by the titration of serum anti-ZEBRA antibodies. Immunological studies were performed on a series of 35 patients randomly selected from the second half of the survey, involving IFN-γ and TNF-α intracellular immunostaining tests performed via flow cytometry analysis in peripheral NK and T cells, in parallel with EBV signature. The effect of the EBV load in the blood or tumor tissue on patient survival was analyzed using univariate and multivariate analyses, combined with an analysis of covariance.ResultsOur study represents the first ever report of the impact of EBV on the clinical outcome of BC patients, regardless of tumor histology or treatment regimen. No correlation was found between: (i) EBV detection in tumor or PBMCs and tumor characteristics; (ii) EBV and other prognostic factors. Notably, patients exhibiting anti-ZEBRA antibodies at high titers experienced poorer overall survival (p = 0.002). Those who recovered from their disease were found to have a measurable EBV DNA load, together with a high frequency of IFN-γ and TNF-α producing PBMCs (p = 0.04), which indicates the existence of a Th1-type polarized immune response in both the tumor and its surrounding tissue.ConclusionsThe replicative form of EBV, as investigated using anti-ZEBRA titers, correlated with poorer outcomes, whereas the latent form of the virus that was measured and quantified using the EBV tumor DNA conferred a survival advantage to BC patients, which could occur through the activation of non-specific anti-tumoral immune responses.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-665) contains supplementary material, which is available to authorized users.

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“…EBV genomes have also been identified in other types of cancer such as breast and gastric carcinomas (4,5). While other herpesviruses, such as cytomegalovirus, are not known to cause cancers, they can nevertheless be present in cancers such as glioblastomas (6).…”

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confidence: 99%

Cellular STAT3 Functions via PCBP2 To Restrain Epstein-Barr Virus Lytic Activation in B Lymphocytes

Koganti

Clark

Zhi

et al. 2015

J Virol

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A major hurdle to killing Epstein-Barr virus (EBV)-infected tumor cells using oncolytic therapy is the presence of a substantial fraction of EBV-infected cells that does not support the lytic phase of EBV despite exposure to lytic cycle-promoting agents. To determine the mechanism(s) underlying this refractory state, we developed a strategy to separate lytic from refractory EBV-positive (EBV ؉ ) cells. By examining the cellular transcriptome in separated cells, we previously discovered that high levels of host STAT3 (signal transducer and activator of transcription 3) curtail the susceptibility of latently infected cells to lytic cycle activation signals. The goals of the present study were 2-fold: (i) to determine the mechanism of STAT3-mediated resistance to lytic activation and (ii) to exploit our findings to enhance susceptibility to lytic activation. We therefore analyzed our microarray data set, cellular proteomes of separated lytic and refractory cells, and a publically available STAT3 chromatin immunoprecipitation sequencing (ChIP-Seq) data set to identify cellular PCBP2 [poly(C)-binding protein 2], an RNA-binding protein, as a transcriptional target of STAT3 in refractory cells. Using Burkitt lymphoma cells and EBV ؉ cell lines from patients with hypomorphic STAT3 mutations, we demonstrate that single cells expressing high levels of PCBP2 are refractory to spontaneous and induced EBV lytic activation, STAT3 functions via cellular PCBP2 to regulate lytic susceptibility, and suppression of PCBP2 levels is sufficient to increase the number of EBV lytic cells. We expect that these findings and the genome-wide resources that they provide will accelerate our understanding of a longstanding mystery in EBV biology and guide efforts to improve oncolytic therapy for EBV-associated cancers. IMPORTANCE Most humans are infected with Epstein-Barr virus (EBV), a cancer-causing virus. While EBV generally persists silently in B lymphocytes, periodic lytic (re)activation of latent virus is central to its life cycle and to most EBV-related diseases. However, a substantial fraction of EBV-infected B cells and tumor cells in a population is refractory to lytic activation. This resistance to lytic activation directly and profoundly impacts viral persistence and the effectiveness of oncolytic therapy for EBV ؉ cancers. To identify the mechanisms that underlie susceptibility to EBV lytic activation, we used host gene and protein expression profiling of separated lytic and refractory cells. We find that STAT3, a transcription factor overactive in many cancers, regulates PCBP2, a protein important in RNA biogenesis, to regulate susceptibility to lytic cycle activation signals. These findings advance our understanding of EBV persistence and provide important leads on devising methods to improve viral oncolytic therapies.

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Possible role of EBV in breast cancer and other unusually EBV-associated cancers

Cited by 36 publications

References 48 publications

Epstein-barr virus may not be associated with breast cancer in Iranian patients

Epstein-barr virus may not be associated with breast cancer in Iranian patients

Epstein-Barr virus infection and clinical outcome in breast cancer patients correlate with immune cell TNF-α/IFN-γ response

Cellular STAT3 Functions via PCBP2 To Restrain Epstein-Barr Virus Lytic Activation in B Lymphocytes

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