Review Article

Epstein-Barr Viral Infection and the Risk for Breast Cancer: A Systematic Review


Background: The prevalence of breast cancer has increased and has currently become one of the most common cancers. Although the majority of the world’s population is infected with Epstein Barr Virus (EBV) during their lives, the severity of symptoms varies and not everyone infected with EBV is diagnosed with cancer. EBV might increase the risk for breast cancer either by activating the HER2/HER3 signaling cascades or by creating a state of prolonged immune stimulation.

Materials and Methods: A systematic search of several electronic databases including PubMed, ScienceDirect, Cochrane, EBSCOhost, JSTOR, and Scopus, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. The primary outcome of this review was to assess the prevalence of people with breast cancer that had a prior EBV infection.  

Results: For this review, 24 case-control studies were accepted. Our analyses included 1.989 breast cancer cases versus 1.034 control cases. EBV was found to be present in 27.9% of breast cancer cases versus 8.02% found in the normal breast tissue of controls. All affected people were women with a mean age was 48.19 years. The most common type of breast cancer found in EBV-infected tissues was invasive breast cancer. Cases were reported sporadically in a wide geographical distribution, and the prevalence varied from 4.6% - 64.1%.

Conclusions: A previous EBV infection might be associated with a higher risk for breast malignancy. The most common type is invasive cancer. It mainly affects women and geographical variances are observed. More studies are necessary to elucidate the role of EBV in the mechanisms of breast cancer. Also, it is crucial to improve the prevention and treatment strategies.

1. World Health Organization. Breast cancer. Published 2021. Accessed April 20, 2022.
2. Vokes EE, Liebowitz DN, Weichselbaum RR. Nasopharyngeal carcinoma. The Lancet. 1997;350(9084):1087-1091.
3. Lawson JS, Heng B. Viruses and breast cancer. Cancers (Basel). 2010;2(2):752-772.
4. Khan G, Hashim MJ. Global burden of deaths from Epstein-Barr virus attributable malignancies 1990-2010. Infect Agents Cancer. 2014;9(1):38.
5. Sterchi DL. Molecular Pathology—In Situ Hybridization. In: Theory and Practice of Histological Techniques. Elsevier; 2008:537-558.
6. Fina F, Romain S, Ouafik L, et al. Frequency and genome load of Epstein–Barr virus in 509 breast cancers from different geographical areas. Br J Cancer. 2001;84(6):783-790.
7. Roa López GA, Suárez JJ, Barato P, et al. Lack of association between Epstein–Barr virus and mammary tumours in dogs. J Vet Res. 2018;62(3):309-315.
8. Lin JH, Tsai CH, Chu JS, et al. Dysregulation of HER2/HER3 Signaling Axis in Epstein-Barr Virus-Infected Breast Carcinoma Cells. J Virol. 2007;81(11):5705-5713.
9. Longnecker R, Neipel F. Introduction to the human γ-herpesviruses. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., eds. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge University Press; 2007. Accessed April 25, 2022.
10. Hoover K, Higginbotham K. Epstein Barr Virus. In: StatPearls. StatPearls Publishing; 2022. Accessed April 29, 2022.
11. Afzal S, Fiaz K, Noor A, et al. Interrelated Oncogenic Viruses and Breast Cancer. Front Mol Biosci. 2022;9:781111.
12. Speck P. Infection of Breast Epithelial Cells With Epstein-Barr Virus Via Cell-to-Cell Contact. Journal of the National Cancer Institute. 2000;92(22):1849-1851.
13. Labrecque LG, Barnes DM, Fentiman IS, et al. Epstein-Barr virus in epithelial cell tumors: a breast cancer study. Cancer Res. 1995;55(1):39-45.
14. Yasui Y, Potter JD, Stanford JL, et al. Breast cancer risk and “delayed” primary Epstein-Barr virus infection. Cancer Epidemiol Biomarkers Prev. 2001;10(1):9-16.
15. Sinclair AJ, Moalwi MH, Amoaten T. Is EBV Associated with Breast Cancer in Specific Geographic Locations? Cancers. 2021;13(4):819.
16. Kang H, Kiess A, Chung CH. Emerging biomarkers in head and neck cancer in the era of genomics. Nat Rev Clin Oncol. 2015;12(1):11-26.
17. Fierti AO, Yakass MB, Okertchiri EA, et al. The Role of Epstein-Barr Virus in Modulating Key Tumor Suppressor Genes in Associated Malignancies: Epigenetics, Transcriptional, and Post-Translational Modifications. Biomolecules. 2022;12(1):127.
18. Kushekhar K, van den Berg A, Nolte I, et al. Genetic Associations in Classical Hodgkin Lymphoma: A Systematic Review and Insights into Susceptibility Mechanisms. Cancer Epidemiol Biomarkers Prev. 2014;23(12):2737-2747.
19. Kazemi Aghdam M, Nadji SA, Khoddami M, et al. Epstein-Barr Virus and Breast Carcinoma in Iran. Jundishapur J Microbiol. 2017;10(10).
20. Lawson JS, Salmons B, Glenn WK. Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein–Barr Virus (EBV). Front Oncol. 2018;8:1.
21. Lefebvre C, Bachelot T, Filleron T, et al. Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis. Mardis ER, ed. PLoS Med. 2016;13(12):e1002201.
22. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
23. Ouzzani M, Hammady H, Fedorowicz Z,et al. Rayyan—a web and mobile app for systematic reviews. Syst Rev. 2016;5(1):210.
24. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Accessed February 23, 2022.
25. Aboulkassim T, Yasmeen A, Akil N, et al. Incidence of Epstein–Barr virus in Syrian women with breast cancer: A tissue microarray study. Human Vaccines & Immunotherapeutics. 2015;11(4):951-955.
26. Al Hamad M, Matalka I, Al Zoubi MS, et al. Human Mammary Tumor Virus, Human Papilloma Virus, and Epstein-Barr Virus Infection Are Associated With Sporadic Breast Cancer Metastasis. Breast Cancer (Auckl). 2020;14:117822342097638.
27. Antonsson A, Bialasiewicz S, Rockett RJ, et al. Exploring the Prevalence of Ten Polyomaviruses and Two Herpes Viruses in Breast Cancer. Buck CB, ed. PLoS ONE. 2012;7(8):e39842.
28. Glenn WK, Heng B, Delprado W, et al. Epstein-Barr Virus, Human Papillomavirus and Mouse Mammary Tumour Virus as Multiple Viruses in Breast Cancer. Mahieux R, ed. PLoS ONE. 2012;7(11):e48788.
29. El-Naby NEH, Hassan Mohamed H, Mohamed Goda A, et al. Epstein-Barr virus infection and breast invasive ductal carcinoma in Egyptian women: A single center experience. J. Egypt. Natl. Cancer Inst. 2017;29(2):77-82.
30. Torfi F, Kamani F, Tavakolian S, et al. Evaluation of association between the frequency of Epstein–Barr virus and cytomegalovirus infection in healthy and tumoral breast samples. Gene Rep. 2021;24(2):101208.
31. Reza MA, Reza MH, Mahdiyeh L, et al. Evaluation Frequency of Merkel Cell Polyoma, Epstein-Barr and Mouse Mammary Tumor Viruses in Patients with Breast Cancer in Kerman, Southeast of Iran. Asian Pac J Cancer Prev. 2015;16(16):7351-7357.
32. Sharifpour C, Makvandi M, Samabafzadeh A, 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(3):687-692.
33. Mostafaei S, Kazemnejad A, Norooznezhad AH, et al. Simultaneous Effects of Viral Factors of Human Papilloma Virus and Epstein-Barr Virus on Progression of Breast and Thyroid Cancers: Application of Structural Equation Modeling. Asian Pac J Cancer Prev. 2020;21(5):1431-1439.
34. 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(1):133-137.
35. Mohammadizadeh F, Zarean M, Abbasi M. Association of Epstein-Barr virus with invasive breast carcinoma and its impact on well-known clinicopathologic parameters in Iranian women. Adv Biomed Res. 2014;3(1):140.
36. Dowran R, Joharinia N, Safaei A, et al. No detection of EBV, BKV and JCV in breast cancer tissue samples in Iran. BMC Res Notes. 2019;12(1):171.
37. Charostad J, Nakhaei M, Azaran A, et al. MiRNA-218 Is Frequently Downregulated in Malignant Breast Tumors: A Footprint of Epstein-Barr Virus Infection. Iran J Pathol. 2021;16(4):376-385.
38. Fessahaye G, Elhassan AM, Elamin EM, et al. Association of Epstein - Barr virus and breast cancer in Eritrea. Infect Agents Cancer. 2017;12:62.
39. Gupta I, Jabeen A, Al-Sarraf R, et al. The co-presence of high-risk human papillomaviruses and Epstein-Barr virus is linked with tumor grade and stage in Qatari women with breast cancer. Hum Vaccin Immunother. 2021;17(4):982-989.

40. Hussein AA. Molecular detection of Epstein Barr Virus in Women with Breast cancer. J Fac Med Baghdad. 2013;55(2):144-148.
41. Zekri ARN, Bahnassy AA, Mohamed WS, et al. Epstein-Barr virus and breast cancer: Epidemiological and Molecular study on Egyptian and Iraqi women. Journal of the Egyptian National Cancer Institute. 2012;24(3):123-131.
42. Khabaz MN. Association of Epstein-Barr virus infection and breast carcinoma. Arch Med Sci. 2013; 9(4): 745–751.
43. Metwally SA, Abo-Shadi MA, Abdel Fattah NF, et al. Presence of HPV, EBV and HMTV Viruses Among Egyptian Breast Cancer Women: Molecular Detection and Clinical Relevance. Infect Drug Resist. 2021; 14: 2327–2339.
44. 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 Oct;54:230-237.
45. Pai T, Gupta S, Gurav M, 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(1):16-22.
46. Richardson AK, Currie MJ, Robinson BA, et al. Cytomegalovirus and Epstein-Barr Virus in Breast Cancer. PLoS One. 2015;10(2):e0118989.
47. Yahia ZA, Adam AA, Elgizouli M, et al. Epstein Barr virus: a prime candidate of breast cancer aetiology in Sudanese patients. Infect Agent Cancer. 2014;9(1):9.
48. Morales-Sánchez A, Molina-Muñoz T, Martínez-López JLE, et al. No association between Epstein-Barr Virus and Mouse Mammary Tumor Virus with Breast Cancer in Mexican Women. Sci Rep. 2013;3:2970.
49. Dunmire SK, Hogquist KA, Balfour HH. Infectious Mononucleosis. In: Münz C, ed. Epstein Barr Virus Volume 1. Vol 390. Current Topics in Microbiology and Immunology. Springer International Publishing; 2015:211-240.
50. Lawson JS, Glenn WK. Catching viral breast cancer. Infect Agents Cancer. 2021;16(1):37.
51. Farahmand M, Monavari SH, Shoja Z, et al. Epstein–Barr virus and risk of breast cancer: a systematic review and meta-analysis. Future Oncol. 2019;15(24):2873-2885.
52. Kadivar M, Monabati A, Joulaee A, et al. Epstein-Barr Virus and Breast Cancer: Lack of Evidence for an Association in Iranian Women. Pathol Oncol Res. 2011;17(3):489-492.
53. Huo Q, Zhang N, Yang Q. Epstein-Barr Virus Infection and Sporadic Breast Cancer Risk: A Meta-Analysis. PLoS ONE. 2012;7(2):e31656.
54. Lorenzetti MA, De Matteo E, Gass H, et al. Characterization of Epstein Barr Virus Latency Pattern in Argentine Breast Carcinoma. PLoS ONE. 2010;5(10):e13603.
55. Hu H, Luo ML, Desmedt C, et al. Epstein–Barr Virus Infection of Mammary Epithelial Cells Promotes Malignant Transformation. EBioMedicine. 2016;9:148-160.
56. Heng YJ, Love S, DeHart JC, et al. The association of infectious mononucleosis and invasive breast cancer in The Health of Women (HOW) Study®. 2022; 29(4):731-739.
57. Bonnet M, Guinebretiere JM, Kremmer E, et al. Detection of Epstein-Barr Virus in Invasive Breast Cancers. J Natl Cancer Inst. 1999;91(16):1376-81.
58. 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(12):1003-5.
IssueVol 17, No 2 (2023) QRcode
SectionReview Article(s)
Epstein-Barr virus (EBV); Systematic review; Breast carcinoma; Breast cancer

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Agolli A, Ishak A, Viswanathan M, Co E, Shivakumar J, Agolli O. Epstein-Barr Viral Infection and the Risk for Breast Cancer: A Systematic Review. Int J Hematol Oncol Stem Cell Res. 2023;17(2):114-125.