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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 4  |  Page : 285-292

Does epstein–barr virus participate in the development of breast cancer? A brief and critical review with molecular evidences

Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur, Pakistan

Date of Submission23-Jun-2020
Date of Acceptance27-Jun-2020
Date of Web Publication30-Dec-2020

Correspondence Address:
Mr. Yasir Hameed
Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_101_20

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The oncogenic potential of Epstein–Barr virus (EBV) has been well studied in human breast cancer (BC) so far but still controversies surround its role. In the present study, we aimed to perform a comprehensive and critical review of the results and methodologies used by the previous studies to identify the association between EBV markers with human breast. We also proposed a criterion based on the Bradford hill postulates of causation and EBV prevalence to evaluate the results of previous studies for proving EBV etiological role in breast cancer. A PubMed search engine-based strategy was implemented to retrieve all the relevant studies. In total, 50 original studies were retrieved. Out of which 20 were case–control studies while others were not. The positivity ratios of EBV detection in breast cancer samples varied study wise. Few studies did not identify the EBV markers in breast cancer while others identified it with different detection positivity ratios varying from 2.9% to 75.8%. Similarly, the EBV detection positivity ratios in normal and benign samples also varied between 0%–35% and 0%–75.8%, respectively. In total, 18 out of 20 case–control studies, the positivity ratios of EBV detection were higher or equal in breast samples as compared to controls, while two case–control studies also report the opposite results. However, the odds ratios and confidence intervals were not reported. The results failed to prove EBV as a potential biomarker of breast cancer but rather suggested its role as a cause-effect or at least co-participant.

Keywords: Breast cancer, Epstein–Barr virus, pubmed, biomarker

How to cite this article:
Usman M, Hameed Y, Ahmad M. Does epstein–barr virus participate in the development of breast cancer? A brief and critical review with molecular evidences. Biomed Biotechnol Res J 2020;4:285-92

How to cite this URL:
Usman M, Hameed Y, Ahmad M. Does epstein–barr virus participate in the development of breast cancer? A brief and critical review with molecular evidences. Biomed Biotechnol Res J [serial online] 2020 [cited 2022 Aug 14];4:285-92. Available from: https://www.bmbtrj.org/text.asp?2020/4/4/285/305633

  Introduction Top

Breast cancer (BC) is the most commonly diagnosed female malignancy in various populations worldwide.[1] Research on breast cancer etiology has primarily focused on the reproductive and other factors responsible for affecting the circulation of sex hormones,[2],[3] as well as on genetic susceptibilities.[4],[5] However, the identified risk factors associated with breast cancer are thought to have insufficient explanatory power in accounting for breast cancer incidence.[6] At present, several research groups are considering other potential routes for breast cancer pathogenesis. The role of viruses in the pathogenesis of various types of cancer is well-known,[7] but viral etiologies have not been considered in-depth for breast cancer. The identification of mouse mammary tumor virus provided evidence for the viral etiology of breast cancer in animals, but similar germline viral sequences detected in humans do not implicate viruses in carcinogenesis.[8]

The association between Epstein–Barr virus (EBV) and breast cancer was initially explored in 1995 by Labrecque et al.[9] Linking EBV to breast cancer has potentially transformative implications, not only in the sense that it could broaden the understanding of breast cancer etiology, but also because it will also be helpful in breast cancer treatment, early diagnosis,[10] and prevention.[11] However, the findings of various studies that have focused on EBV's role in breast cancer vary substantially.[12],[13] To a degree, these inconsistencies are attributable to persistent methodological problems, including technical challenges associated with localizing EBV into tumor cells; and the tendency to disregard the epidemiological perspective, which may be helpful in elucidating variability in EBV prevalence across all the studies.[14]

With these considerations in mind, as well as the well-documented complexity of the relationship between EBV and other malignancies, it is important to review the molecular evidence for EBV's relationship with breast cancer in the context of EBV pathobiology. In addition, it will be worthwhile to explore the epidemiology of EBV related cancers, as well as the current laboratory technologies used for EBV detection.

  Epstein–Barr Virus Biology Top

EBV is a γ herpesvirus comprised of184-kb DNA genome, of which it encodes approximately 100 different genes.[15] Saliva is the main transmission route of this virus,[16] which usually leads to primary infection in the oral mucosa as a subclinical illness.[17] Primary EBV infection has a replicative (lytic) component, which is marked by the production of new virions. After the immune system traps the virus, the latent infection occurs within a subset of B cells such that each B cell in a healthy individual carries 1–50 EBV genomes.[18] This long-life latent infection is supported by the ability of the EBV virus to evade host immune surveillance.[19],[20] It achieves this by expressing several factors: first, six nuclear antigens (EBNA-1,-2,-3a,-3b,-3c, and-LP); second, three latent membrane proteins (LMP-1, 2a, and-2b); and finally, two abundant, untranslated RNAs Epstein–Barr virus (EBV)-encoded small RNA (EBER-1 and-2). The periodic lytic infection in the oral mucosa causes virion shedding in saliva, after which they can be transmitted to other human hosts.

  Relevance of Epstein–Barr Virus in Cancer Top

Due to the balance of EBV virion production, persistence, and immune control, most of the world's population tolerates lifetime EBV infection with no adverse health effects. However, EBV etiology has been linked with several cancers, including African Burkitt lymphoma, in which its role was initially described.[21] Relationships have also been observed between EBV etiology and AIDS, Hodgkin lymphoma, nasal natural killer/T-cell lymphoma, nasopharyngeal carcinoma (NPC), leiomyosarcoma, posttransplant lymphoproliferative disorder, lymphoepithelioma-like squamous cell malignancies, and gastric adenocarcinoma.[14] EBV is known to play an important role in the development of various cancers for different reasons.[22] The main reasons are given as follows:

  1. LMP1, a viral gene, acts as a transforming oncogene in rodent fibroblasts[23],[24]
  2. The virus has been immortalized in B-cell lines in vitro
  3. EBV infection can lead to lymphoma formation in some primates, as well as in immunosuppressed persons
  4. In EBV-associated tumors, the viral genome is almost always present as an episome, which is an inherently unstable extrachromosomal form[25] that may be lost from a proliferating cell population
  5. Most EBV-associated cancers harbor a monoclonal form of EBV genome in each tumor cell.[26] This indicates that infection either precede malignant transformation or confers an advantage to an already malignant cell and its progeny
  6. Transfection of the p31 subfragment of EBV immortalizes human epithelial cells such as mammary epithelium[27]
  7. In NPC, EBV-specific antibody titers correlate with tumor burden.[28]

At present, the search for viral etiology in human breast cancer remains controversial because of the inconsistencies in the results reproducibility.[29] This controversy is further aggravated by the fact that the scientific community demands proof of the viral etiology in breast cancer.

The first-ever study carried out in 1995 by Labrecque et al.[9] has shown the correlation between EBV infection and breast cancer in the United Kingdom (UK) population. However, the EBV genome was only detected in 21% (19/91) of breast cancer tissues.

After 1990, many researchers performed the detection of HPV in breast cancer tissue specimens utilizing different methodologies but still, the outcomes are controversial. In this article, we aimed to provide a comprehensive review of published articles which associated EBV infections with breast cancer, evaluation of the strengths, weakness, and the consistency of their results with Bradford hill postulates of causation (which provide epidemiologic evidence of a causal relationship between a presumed cause and an observed effect) will also remain the major focus of this review article.

  Methodology Top

Methodology of the present work has been divided into the following two phases.

Literature search

A thorough and extensive search was launched through PubMed search engine to identify all the relevant articles associating the EBV with breast cancer. The “Breast cancer” AND “Epstein–Barr Virus” was used as keywords while “Herpesviridae” AND “Breast neoplasia” were selected as medical subject headings (MeSH) terms. The MeSH terms and keywords were combined during the completion of the search process. In total of 666 original articles were found on PubMed before April 2020, with the “Original Article” filter [Figure 1].
Figure 1: Overview of the methodology implemented during the present study

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Relevant data extraction

Of total 606 original articles, the relevant articles with desired information were extracted initially by reading the title, abstract, and then the complete article [Figure 1].

  Results Top

In total, 50 original molecular studies [Figure 2] associating EBV with human breast cancer were retrieved after the extensive literature search. Out of which 20 were the case–control studies where both cancers samples and normal or benign controls were analyzed while the remaining 30 studies either analyzed cancerous or normal and benign samples individually. [Table 1] lists these studies and offers details about the target population, the technique used for viral genome identification, the target gene name, the number of control, benign, and cancer samples screened and EBV detection positivity ratios in each control, benign, and cancer group.
Figure 2: Comparison graph between the numbers (No) of the studies carried out in each population on Epstein–Barr virus in human breast

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Table 1: Summary of the Epstein-Barr virus detection and positivity rate in normal and breast cancer samples relative to the different selected articles

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Majority of the studies [9,30-68] used the polymerase chain reaction (PCR) amplification for EBV detection, relying on standard, commercially available primers utilized to screen EBV in various other cancer subtypes.[31],[32],[35],[37] These primer sets target the BamH1W, BamHIc, Pol, BXLF2, LLW1, LMP1, EBNA1, LMP2, BZLF1, EBER, and BMRF1 regions of EBV, which are responsible for encoding most of the proteins in the viral capsid, and they more accurately detected all the EBV subtypes. Other studies used numerous other EBV detection techniques including immunohistochemistry (IHC),[34],[35],[41],[43],[45],[48],[52],[58],[60],[61],[66],[68],[69],[70],[71],[72] in situ hybridization (ISH),[35],[44],[52],[55],[56],[58],[60],[66],[69],[72],[73],[74],[75],[76],[77] restriction fragment length polymorphism,[39] enzyme-linked immunosorbent assay,[39] tissue microarray analysis,[46] illumina dye sequencing,[78] and Southern blotting.[52],[67],[72]

The reported positivity ratios of EBV detection in breast cancer tissue were ranged from 0%[31],[34],[54],[62],[69],[73],[74],[75],[76],]78] to 75.8%.[67] The positivity ratio of EBV detection in normal breast samples ranged from 0%[34],[40],[56],[61],[67],[79] to 35%.[37] Contrastingly, the positivity ratio of EBV detection in benign breast samples ranged from 0%[31],[34],[36],[43],[60],[61],[77],[80] to 50%.[67]

  Discussion Top

A total of 50 original molecular studies [Figure 2] associating EBV with normal, benign, and cancerous breast tissues were examined in the present study. The aim of this review was to evaluate and compare the results and methodologies of these studies used for EBV detection. And demonstrate if the presence of EBV markers were higher in cancerous samples than benign cases and controls or the results produced by these studies follow all the Bradford hill postulates of causation was proposed as the main criterion in the present study for investigating the etiological role of EBV in breast cancer pathogenesis.

The results of the present study are controversial as they do not reject or accept the etiological role of EBV in the pathogenesis of breast cancer. The circumstance of EBV detection positivity in breast cancer can be criticized, but the elements that are clearly demonstrated in a number of cases are also relevant.

In 1995, Labrecque et al.[9] were the first to report the presence of EBV in breast cancer patients of the UK. They identified the EBV genome in 21% (19/91) of breast cancer tissues by utilizing qPCR and IHC techniques. Two other studies,[69],[75] conducted in the 1990s in China and the United States did not identify EBV markers in any of the breast cancer tissues they were investigating. Contrastingly, in 1999, Bonnet et al.[52] reported the 51% EBV detection positivity in breast cancer patients of France conventional PCR, Southern blotting, ISH, and IHC techniques. In 2005, Kalkan et al. carried out a study[63] based on the Turkish population found 23% positivity of EBV detection in Turkish breast cancer patients suggesting that EBV infection may be involved in breast cancer pathogenesis in the Turkish population.

Since then, various studies have been carried out worldwide, some of which failed to identify EBV markers in breast tissue samples, while others identified it with different positivity ratios, varying between 0% and 75.8%. The reasons for such population-specific inequalities in EBV detection positivity ratios may include differences in socially controllable factors such as participation in the screening tests and health-seeking behavior, as well as differential access to health services such as cancer treatment. Genetic and other “non-modifiable” biological factors may also contribute to the existing inequalities.

The EBV positivity ratio pattern in cancerous and normal or benign tissue samples do not meet the requisite criteria and some of Bradford hill postulates of causation[81] including (strength, consistency, and specificity) to declare the EBV as a potential biomarker of the breast cancer. However, the limitations and some issues in summarized studies related to the possibility of false-positive and false-negative results have been discussed below.

  Possible Causes of False-Negative Results Top

Several studies did not find any EBV markers in breast tissue samples (cancerous and normal or benign), so it is important to evaluate whether these results are genuine or they might be the outcome of low-quality DNA being utilized for testing. One study neglected to perform DNA quality testing with internal controls, and so there was no way to confirm their negative results.[34] Another possible cause of false negatives, which was not reported in any of the studies included in this review, involves the extraction of DNA from a small volume of tissue in which viral load can be too low to amplify.

  Possible Causes of False-Positive Results Top

The risk of contamination in the PCR reaction can never be ruled out. Some studies[48],[49],[51],[59],[64],[65],[74] used real-time PCR, which is more prone to the contamination and can produce false-positive results.[82] Even though they cited good laboratory practices so contamination was unlikely but cannot be completely ruled out.

Comparison of Normal, Benign, and Malignant Tissues

Case–control studies are important when seeking to establish an association between a causative agent and a disease. However, most of the studies included in this review examined only malignant tissues, which prevented direct comparison with normal and benign tissues.[9],[42],[44],[45],[46],[47],[48],[49],[50],[51],[52],[54],[55],[58],[59],[62],[64],[65],[66],[68],[69],[70],[71],[72],[73],[74],[75],[76],[78],[83] From all the case–control studies,[31],[32],[34],[35],[36],[37],[38],[39],[40],[41],[43],[53],[56],[60],[61],[63],[67],[77],[79],[80] where normal or benign breast tissues were also examined along with the diseased samples, most of the studies have revealed a higher EBV detection positivity ratio in malignant tissues[32],[35],[37],[40],[41],[43],[53],[56],[60],[61],[67],[77],[79],[80] in comparison to normal or benign, however, two studies[36],[63] have also shown the higher EBV positivity ratio in normal or benign tissues as compared to malignant [Table 1].

  Conclusion Top

The results are controversial. They suggested EBV as a cause-effective participant or at least as a co-participant in breast cancer pathogenesis rather than the potential biomarker.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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