|Year : 2020 | Volume
| Issue : 4 | Page : 285-292
Does epstein–barr virus participate in the development of breast cancer? A brief and critical review with molecular evidences
Muhammad Usman, Yasir Hameed, Mukhtiar Ahmad
Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
|Date of Submission||23-Jun-2020|
|Date of Acceptance||27-Jun-2020|
|Date of Web Publication||30-Dec-2020|
Mr. Yasir Hameed
Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur
Source of Support: None, Conflict of Interest: None
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 2021 Dec 8];4:285-92. Available from: https://www.bmbtrj.org/text.asp?2020/4/4/285/305633
| Introduction|| |
Breast cancer (BC) is the most commonly diagnosed female malignancy in various populations worldwide. Research on breast cancer etiology has primarily focused on the reproductive and other factors responsible for affecting the circulation of sex hormones,, as well as on genetic susceptibilities., However, the identified risk factors associated with breast cancer are thought to have insufficient explanatory power in accounting for breast cancer incidence. 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, 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.
The association between Epstein–Barr virus (EBV) and breast cancer was initially explored in 1995 by Labrecque et al. 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, and prevention. However, the findings of various studies that have focused on EBV's role in breast cancer vary substantially., 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.
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|| |
EBV is a γ herpesvirus comprised of184-kb DNA genome, of which it encodes approximately 100 different genes. Saliva is the main transmission route of this virus, which usually leads to primary infection in the oral mucosa as a subclinical illness. 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. This long-life latent infection is supported by the ability of the EBV virus to evade host immune surveillance., 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|| |
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. 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. EBV is known to play an important role in the development of various cancers for different reasons. The main reasons are given as follows:
- LMP1, a viral gene, acts as a transforming oncogene in rodent fibroblasts,
- The virus has been immortalized in B-cell lines in vitro
- EBV infection can lead to lymphoma formation in some primates, as well as in immunosuppressed persons
- In EBV-associated tumors, the viral genome is almost always present as an episome, which is an inherently unstable extrachromosomal form that may be lost from a proliferating cell population
- Most EBV-associated cancers harbor a monoclonal form of EBV genome in each tumor cell. This indicates that infection either precede malignant transformation or confers an advantage to an already malignant cell and its progeny
- Transfection of the p31 subfragment of EBV immortalizes human epithelial cells such as mammary epithelium
- In NPC, EBV-specific antibody titers correlate with tumor burden.
At present, the search for viral etiology in human breast cancer remains controversial because of the inconsistencies in the results reproducibility. 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. 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|| |
Methodology of the present work has been divided into the following two phases.
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|
Click here to view
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|| |
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|
Click here to view
|Table 1: Summary of the Epstein-Barr virus detection and positivity rate in normal and breast cancer samples relative to the different selected articles|
Click here to view
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.,,, 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),,,,,,,,,,,,,,,, in situ hybridization (ISH),,,,,,,,,,,,,,, restriction fragment length polymorphism, enzyme-linked immunosorbent assay, tissue microarray analysis, illumina dye sequencing, and Southern blotting.,,
The reported positivity ratios of EBV detection in breast cancer tissue were ranged from 0%,,,,,,,,,]78] to 75.8%. The positivity ratio of EBV detection in normal breast samples ranged from 0%,,,,, to 35%. Contrastingly, the positivity ratio of EBV detection in benign breast samples ranged from 0%,,,,,,, to 50%.
| Discussion|| |
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. 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,, 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. 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 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 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|| |
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. 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|| |
The risk of contamination in the PCR reaction can never be ruled out. Some studies,,,,,, used real-time PCR, which is more prone to the contamination and can produce false-positive results. 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.,,,,,,,,,,,,,,,,,,,,,,,,,,,,, From all the case–control studies,,,,,,,,,,,,,,,,,,,, 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,,,,,,,,,,,,, in comparison to normal or benign, however, two studies, have also shown the higher EBV positivity ratio in normal or benign tissues as compared to malignant [Table 1].
| Conclusion|| |
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.
| References|| |
Akram M, Iqbal M, Daniyal M, Khan AU. Awareness and current knowledge of breast cancer. Biol Res 2017;50:33.
Zhao Y, Dong Q, Li J, Zhang K, Qin J, Zhao J, et al
. Corrigendum to targeting cancer stem cells and their niche: Perspectives for future therapeutic targets and strategies. Semin Cancer Biol 2019;57:117.
Hulka BS, Moorman PG. Breast cancer: Hormones and other risk factors. Maturitas 2008;61:203-13.
Rebbeck TR. Inherited genetic predisposition in breast cancer. A population-based perspective. Cancer 1999;86:2493-501.
Martin AM, Weber BL. Genetic and hormonal risk factors in breast cancer. J Natl Cancer Inst 2000;92:1126-35.
Madigan MP, Ziegler RG, Benichou J, Byrne C, Hoover RN. Proportion of breast cancer cases in the United States explained by well-established risk factors. J Natl Cancer Inst 1995;87:1681-5.
Morales-Sánchez A, Fuentes-Pananá EM. Human viruses and cancer. Viruses 2014;6:4047-79.
Pogo BG, Holland JF. Possibilities of a viral etiology for human breast cancer. A review. Biol Trace Elem Res 1997;56:131-42.
Labrecque LG, Barnes DM, Fentiman IS, Griffin BE. Epstein-Barr virus in epithelial cell tumors: A breast cancer study. Cancer Res 1995;55:39-45.
Fan H, Gulley ML. Epstein-Barr viral load measurement as a marker of EBV-related disease. Molecular Diag 2001;6:279-89.
Khanna R, Moss DJ, Burrows SR. Vaccine strategies against Epstein-Barr virus-associated diseases: Lessons from studies on cytotoxic T-cell-mediated immune regulation. Immunol Rev 1999;170:49-64.
Gaffey MJ, Frierson HF Jr., Mills SE, Boyd JC, Zarbo RJ, Simpson JF, et al
. Medullary carcinoma of the breast. Identification of lymphocyte subpopulations and their significance. Mod Pathol 1993;6:721-8.
Horiuchi K, Mishima K, Ohsawa M, Aozasa K. Carcinoma of stomach and breast with lymphoid stroma: Localisation of Epstein-Barr virus. J Clin Pathol 1994;47:538-40.
Hsu JL, Glaser SL. Epstein-Barr virus-associated malignancies: Epidemiologic patterns and etiologic implications. Crit Rev Oncol Hematol 2000;34:27-53.
Ismail A, Osman I, Husain NE LMP1 Immunohistochemistry in Non-Hodgkin's Lymphoma of Sudanese Cases. Open J Pathology 2016;6:79.
Wolf H, Bogedain C, Schwarzmann F. Epstein-Barr virus and its interaction with the host. Intervirology 1993;35:26-39.
Humans IWGotEoCRt, Cancer IAfRo. Epstein-Barr Virus and Kaposi's Sarcoma Herpesvirus/Human Herpesvirus. 8. Vol 70. World Health Organization; 1997.
Gulley ML. Molecular diagnosis of Epstein-Barr virus-related diseases. J Mol Diagn 2001;3:1-10.
Glaser SL, Lin RJ, Stewart SL, Ambinder RF, Jarrett RF, Brousset P, et al
. Epstein-Barr virus-associated Hodgkin's disease: Epidemiologic characteristics in international data. Int J Cancer 1997;70:375-82.
Khanna R, Burrows SR, Moss DJ. Immune regulation in Epstein-Barr virus-associated diseases. Microbiol Rev 1995;59:387-405.
Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet (London, England) 1964;1:702-3.
Rickinson A Epstein-Barr virus. Virology 2001. p. 2573-627.
Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 1985;43:831-40.
Moorthy RK, Thorley-Lawson DA. Biochemical, genetic, and functional analyses of the phosphorylation sites on the Epstein-Barr virus-encoded oncogenic latent membrane protein LMP-1. J Virol 1993;67:2637-45.
Staal SP, Ambinder R, Beschorner WE, Hayward GS, Mann R. A survey of Epstein-Barr virus DNA in lymphoid tissue. Frequent detection in Hodgkin's disease. Am J Clin Pathol 1989;91:1-5.
Gulley ML, Eagan PA, Quintanilla-Martinez L, Picado AL, Smir BN, Childs C, et al
. Epstein-Barr virus DNA is abundant and monoclonal in the Reed-Sternberg cells of Hodgkin's disease: Association with mixed cellularity subtype and Hispanic American ethnicity. Blood 1994;83:1595-602.
Gao Y, Lu YJ, Xue SA, Chen H, Wedderburn N, Griffin BE. Hypothesis: A novel route for immortalization of epithelial cells by Epstein-Barr virus. Oncogene 2002;21:825-35.
Ho HC, Ng MH, Kwan HC, Chau JC. Epstein-Barr-virus-specific IgA and IgG serum antibodies in nasopharyngeal carcinoma. Br J Cancer 1976;34:655-60.
Mant C, Hodgson S, Hobday R, D'Arrigo C, Cason J. A viral aetiology for breast cancer: Time to re-examine the postulate. Intervirology 2004;47:2-13.
Golrokh Mofrad M, Kazeminezhad B, Faghihloo E. Prevalence of Epstein-Barr virus (EBV) in Iranian Breast Carcinoma Patients. Asian Pac J Cancer Prev 2020;21:133-7.
Dowran R, Joharinia N, Safaei A, Bakhtiyarizadeh S, Alidadi Soleimani A, Alizadeh R, et al
. No detection of EBV, BKV and JCV in breast cancer tissue samples in Iran. BMC Res Notes 2019;12:171.
Sharifpour C, Makvandi M, Samarbafzadeh A, Talaei-Zadeh A, Ranjbari N, Nisi N, et al
. Frequency of Epstein-Barr Virus DNA in formalin-fixed paraffin-embedded tissue of patients with ductal breast carcinoma Asian Pac J Cancer Prev 2019;20:687-92.
Reza MA, Reza MH, Mahdiyeh L, Mehdi F, Hamid ZN. Evaluation frequency of merkel cell polyoma, epstein-barr and mouse mammary tumor viruses in patients with breast cancer in Kerman, Southeast of Iran. Asian Pacific journal of cancer prevention. APJCP 2015;16:7351-7.
Kadivar M, Monabati A, Joulaee A, Hosseini N. Epstein-Barr virus and breast cancer: Lack of evidence for an association in Iranian women. Pathol Oncol Res 2011;17:489-92.
Fessahaye G, Elhassan AM, Elamin EM, Adam AAM, Ghebremedhin A, Ibrahim ME. Association of Epstein-Barr virus and breast cancer in Eritrea. Infect Agent Cancer 2017;12:62.
Lawson JS, Glenn WK. Multiple oncogenic viruses are present in human breast tissues before development of virus associated breast cancer. Infect Agent Cancer 2017;12:55.
Glenn WK, Heng B, Delprado W, Iacopetta B, Whitaker NJ, Lawson JS. Epstein-Barr virus, human papillomavirus and mouse mammary tumour virus as multiple viruses in breast cancer. PLoS One 2012;7:e48788.
Glenn WK, Whitaker NJ, Lawson JS. High risk human papillomavirus and Epstein-Barr virus in human breast milk. BMC Res Notes 2012;5:477.
Zhang W, Wang MY, Wei XL, Lin Y, Su FX, Xie XM, et al
. Associations of Epstein-Barr Virus DNA in PBMCs and the Subtypes with Breast Cancer Risk. J Cancer 2017;8:2944-9.
Naushad W, Surriya O, Sadia H. Prevalence of EBV, HPV and MMTV in Pakistani breast cancer patients: A possible etiological role of viruses in breast cancer. Infect Genet Evol 2017;54:230-7.
El-Naby NEH, Hassan Mohamed H, Mohamed Goda A, El Sayed Mohamed A. Epstein-Barr virus infection and breast invasive ductal carcinoma in Egyptian women: A single center experience. J Egypt Natl Canc Inst 2017;29:77-82.
El-Shinawi M, Mohamed HT, Abdel-Fattah HH, Ibrahim SA, El-Halawany MS, Nouh MA, et al
. Inflammatory and non-inflammatory breast cancer: A potential role for detection of multiple viral DNAs in disease progression. Ann Surg Oncol 2016;23:494-502.
Fawzy S, Sallam M, Awad NM. Detection of Epstein-Barr virus in breast carcinoma in Egyptian women. Clin Biochem 2008;41:486-92.
Hu H, Luo ML, Desmedt C, Nabavi S, Yadegarynia S, Hong A, et al
. Epstein-Barr virus infection of mammary epithelial cells promotes malignant transformation. EBioMedicine 2016;9:148-60.
Al Moustafa AE, Al-Antary N, Aboulkassim T, Akil N, Batist G, Yasmeen A. Co-prevalence of Epstein-Barr virus and high-risk human papillomaviruses in Syrian women with breast cancer. Human Vaccines Immunotherapeutics 2016;12:1936-9.
Aboulkassim T, Yasmeen A, Akil N, Batist G, Al Moustafa AE. Incidence of Epstein-Barr virus in Syrian women with breast cancer: A tissue microarray study. Hum Vaccin Immunother 2015;11:951-5.
Morales-Sánchez A, Molina-Muñoz T, Martínez-López JL, Hernández-Sancén P, Mantilla A, Leal YA, et al
. No association between Epstein-Barr Virus and Mouse Mammary Tumor Virus with breast cancer in Mexican women. Sci Rep 2013;3:2970.
Murray PG, Lissauer D, Junying J, Davies G, Moore S, Bell A, et al
. Reactivity with A monoclonal antibody to Epstein-Barr virus (EBV) nuclear antigen 1 defines a subset of aggressive breast cancers in the absence of the EBV genome. Cancer Res 2003;63:2338-43.
Mazouni C, Fina F, Romain S, Ouafik LH, Bonnier P, Martin PM. Outcome of Epstein-Barr virus-associated primary breast cancer. Mol Clin Oncol 2015;3:295-8.
Mazouni C, Fina F, Romain S, Ouafik L, Bonnier P, Brandone JM, et al
. Epstein-Barr virus as a marker of biological aggressiveness in breast cancer. Br J Cancer 2011;104:332-7.
Arbach H, Viglasky V, Lefeu F, Guinebretière JM, Ramirez V, Bride N, et al
. Epstein-Barr virus (EBV) genome and expression in breast cancer tissue: Effect of EBV infection of breast cancer cells on resistance to paclitaxel (Taxol). J Virol 2006;80:845-53.
Bonnet M, Guinebretiere JM, Kremmer E, Grunewald V, Benhamou E, Contesso G, et al
. Detection of Epstein-Barr virus in invasive breast cancers. J Natl Cancer Inst 1999;91:1376-81.
Richardson AK, Currie MJ, Robinson BA, Morrin H, Phung Y, Pearson JF, et al
. Cytomegalovirus and Epstein-Barr virus in breast cancer. PLoS One 2015;10:e0118989.
Marrão G, Habib M, Paiva A, Bicout D, Fallecker C, Franco S, et al
. Epstein-Barr virus infection and clinical outcome in breast cancer patients correlate with immune cell TNF-α/IFN-γ response. BMC Cancer 2014;14:665-5.
Yahia ZA, Adam AA, Elgizouli M, Hussein A, Masri MA, Kamal M, et al
. Epstein Barr virus: A prime candidate of breast cancer aetiology in Sudanese patients. Infect Agent Cancer 2014;9:9.
Zekri AR, Bahnassy AA, Mohamed WS, El-Kassem FA, El-Khalidi SJ, Hafez MM, et al
. Epstein-Barr virus and breast cancer: Epidemiological and molecular study on Egyptian and Iraqi women. J Egypt Natl Canc Inst 2012;24:123-31.
Baltzell K, Buehring GC, Krishnamurthy S, Kuerer H, Shen HM, Sison JD. Epstein-Barr virus is seldom found in mammary epithelium of breast cancer tissue using in situ
molecular methods. Breast Cancer Res Treat 2012;132:267-74.
Hachana M, Amara K, Ziadi S, Romdhane E, Gacem RB, Trimeche M. Investigation of Epstein-Barr virus in breast carcinomas in Tunisia. Pathol Res Pract 2011;207:695-700.
Aguayo F, Khan N, Koriyama C, González C, Ampuero S, Padilla O, et al
. Human papillomavirus and Epstein-Barr virus infections in breast cancer from chile. Infect Agent Cancer 2011;6:7.
Lorenzetti MA, De Matteo E, Gass H, Martinez Vazquez P, Lara J, Gonzalez P, et al
. Characterization of Epstein-Barr virus latency pattern in Argentine breast carcinoma. PLoS One 2010;5:e13603.
Ribeiro-Silva A. Epstein-Barr virus in breast carcinoma in Argentina. Arch Pathol Lab Med 2005;129:1088.
Kulka J, Kovalszky I, Svastics E, Berta M, Füle T Lymphoepithelioma-like carcinoma of the breast: not Epstein-Barr virus-, but human papilloma virus-positive. Hum Pathol 2008;39:298-301.
Kalkan A, Ozdarendeli A, Bulut Y, Yekeler H, Cobanoglu B, Doymaz MZ. Investigation of Epstein-Barr virus DNA in formalin-fixed and paraffin- embedded breast cancer tissues. Medical principles and practice: Int J Kuwait Univ Health Sci Centre 2005;14:268-71.
Perkins RS, Sahm K, Marando C, Dickson-Witmer D, Pahnke GR, Mitchell M, et al
. Analysis of Epstein-Barr virus reservoirs in paired blood and breast cancer primary biopsy specimens by real time PCR. Breast Cancer Res 2006;8:R70.
Thorne LB, Ryan JL, Elmore SH, Glaser SL, Gulley ML. Real-time PCR measures Epstein-Barr Virus DNA in archival breast adenocarcinomas. Diagn Mol Pathol 2005;14:29-33.
Lau SK, Chen YY, Berry GJ, Yousem SA, Weiss LM. Epstein-Barr virus infection is not associated with fibroadenomas of the breast in immunosuppressed patients after organ transplantation. Mod Pathol 2003;16:1242-7.
Tsai JH, Tsai CH, Cheng MH, Lin SJ, Xu FL, Yang CC. Association of viral factors with non-familial breast cancer in Taiwan by comparison with non-cancerous, fibroadenoma, and thyroid tumor tissues. J Med Virol 2005;75:276-81.
Herrmann K, Niedobitek G. Lack of evidence for an association of Epstein-Barr virus infection with breast carcinoma. Breast Cancer Res 2003;5:R13-7.
Chu JS, Chen CC, Chang KJ. In situ
detection of Epstein-Barr virus in breast cancer. Cancer Lett 1998;124:53-7.
Glaser SL, Canchola AJ, Keegan TH, Clarke CA, Longacre TA, Gulley ML. Variation in risk and outcomes of Epstein-Barr virus-associated breast cancer by epidemiologic characteristics and virus detection strategies: An exploratory study. Cancer Causes Control 2017;28:273-87.
Ballard AJ. Epstein-Barr virus infection is equally distributed across the invasive ductal and invasive lobular forms of breast cancer. Pathol Res Pract 2015;211:1003-5.
Chu PG, Chang KL, Chen YY, Chen WG, Weiss LM. No significant association of Epstein-Barr virus infection with invasive breast carcinoma. Am J Pathol 2001;159:571-8.
Fonseca R, Tomás AR, André S. Absence of Epstein-Barr virus EBER transcripts in male breast cancer. Virchows Arch 2005;447:113-4.
Davies AJ, Lee AM, Taylor C, Clear AJ, Goff LK, Iqbal S, et al
. A limited role for TP53 mutation in the transformation of follicular lymphoma to diffuse large B-cell lymphoma. Leukemia 2005;19:1459-65.
Deshpande CG, Badve S, Kidwai N, Longnecker R. Lack of expression of the Epstein-Barr Virus (EBV) gene products, EBERs, EBNA1, LMP1, and LMP2A, in breast cancer cells. Lab Invest 2002;82:1193-9.
Glaser SL, Ambinder RF, DiGiuseppe JA, Horn-Ross PL, Hsu JL. Absence of Epstein-Barr virus EBER-1 transcripts in an epidemiologically diverse group of breast cancers. Int J Cancer 1998;75:555-8.
Pai T, Gupta S, Gurav M, Nag S, Shet T, Patil A, et al
. Evidence for the association of Epstein-Barr Virus in breast cancer in Indian patients using in-situ hybridization technique. Breast J 2018;24:16-22.
Fuentes-Pananá EM, Larios-Serrato V, Méndez-Tenorio A, Morales-Sánchez A, Arias CF, Torres J. Assessment of Epstein-Barr virus nucleic acids in gastric but not in breast cancer by next-generation sequencing of pooled Mexican samples. Mem Inst Oswaldo Cruz 2016;111:200-8.
Reza MA, Reza MH, Mahdiyeh L, Mehdi F, Hamid ZN. Evaluation frequency of merkel cell polyoma, Epstein-Barr and mouse mammary tumor viruses in patients with breast cancer in Kerman, Southeast of Iran. Asian Pacific J Cancer Prevention 2015;16:7351-7.
Golrokh Mofrad M, Kazeminezhad B, Faghihloo E. Prevalence of Epstein-Barr virus (EBV) in Iranian breast carcinoma patients. Asian Pacific J Cancer Prevention 2020;21:133-7.
Fedak KM, Bernal A, Capshaw ZA, Gross S. Applying the Bradford Hill criteria in the 21st
century: How data integration has changed causal inference in molecular epidemiology. Emerg Themes Epidemiol 2015;12:14.
Corless CE, Guiver M, Borrow R, Edwards-Jones V, Kaczmarski EB, Fox AJ. Contamination and sensitivity issues with a real-time universal 16S rRNA PCR. J Clin Microbiol 2000;38:1747-52.
Baltzell K, Buehring GC, Krishnamurthy S, Kuerer H, Shen HM, Sison JD. Limited evidence of human papillomavirus in [corrected] breast tissue using molecular in situ
methods. Cancer 2012;118:1212-20.
[Figure 1], [Figure 2]