Next Article in Journal
Telemedicine Improves HCV Elimination among Italian People Who Use Drugs: An Innovative Therapeutic Model to Increase the Adherence to Treatment into Addiction Care Centers Evaluated before and during the COVID-19 Pandemic
Previous Article in Journal
An Insight Based on Computational Analysis of the Interaction between the Receptor-Binding Domain of the Omicron Variants and Human Angiotensin-Converting Enzyme 2
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Epstein–Barr Virus Association with Breast Cancer: Evidence and Perspectives

1
Programa de Virología, Laboratorio de Oncovirología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
2
Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile
3
Center for Radiological Research, Columbia University Medical Center, New York, NY 10032, USA
4
Universidad de Tarapacá, Arica 1000000, Chile
*
Author to whom correspondence should be addressed.
Submission received: 17 March 2022 / Revised: 11 May 2022 / Accepted: 12 May 2022 / Published: 24 May 2022

Abstract

:

Simple Summary

Epstein–Barr virus (EBV) is a very ubiquitous and persistent virus present in ~90% of the world population. The infection is generally asymptomatic during the lifetime, though it can cause lymphoid tumors and carcinomas in some subjects. The role of EBV in breast cancer (BC) has yet to be determined. In this review, we present the historical background and scientific evidence regarding the presence and potential role of EBV in this malignancy and we propose possible molecular mechanisms. Knowledge of EBV´s role in BC will contribute to establishing prevention strategies, early detection, and control of this highly aggressive and prevalent malignancy.

Abstract

Epstein–Barr virus (EBV) is an enveloped DNA virus that belongs to the gamma Herpesviridae family. The virus establishes a latent/lytic persistent infection, though it can be involved in cancer development in some subjects. Indeed, evidence supports an etiological role of EBV in undifferentiated nasopharyngeal carcinoma (NPC), a subset of gastric carcinomas and lymphomas. Additionally, EBV has been detected in breast carcinomas (BCs) although its role has not been established. In this review, we summarize epidemiological information regarding the presence of EBV in BC and we propose mechanistic models. However, additional epidemiological and experimental evidence is warranted to confirm these models.

1. Introduction

Breast cancer (BC) is the most prevalent malignancy in both developing and industrialized countries [1]. Long-term exposure to risk factors, variable socioeconomic status, lack of primary attention facilities, and genetic factors, all contribute to the burden of BC [2,3]. Women are the most affected gender, although male BC cases have also been reported in some regions [4,5,6]. In 2020, BC ranked first among the 36 most common cancer types in 159 countries with 2,261,419 cases, accounting for an overall incidence of 11.7% of diagnosed cases. High-income regions such as Australia/New Zealand showed the highest age-standardized incidence rate (95.5/100,000) while South Central Asia had the lowest (26.2/100,000) [1]. Despite the current efforts to prevent this disease, an annual increase of 2% is expected to occur by 2030 [7]. The 5-year relative survival rate varies depending on the geographic region [8]. In 2020, BC ranked fifth among the 36 most common cancer types in 110 countries with 684,996 deaths, representing 6.9% of total cancer deaths. Melanesia showed the highest age-standardized mortality rate (27.5/100,000) while Eastern Asia showed the lowest (9.8/100,000). These data reflect the worldwide impact that BC represents and highlight the necessity to overcome health care barriers and promote access to screening strategies for BC prevention, early detection, and treatment [1,9].
Substantial efforts have been made to understand BC’s etiology. Some risk factors have been identified, such as female gender, germline mutations in BRCA1 or BRCA2 genes, first degree relatives with positive BC history, obesity, oral contraceptive usage, early menarche, late menopause, elderly nulliparity, sedentary lifestyle, alcohol intake, tobacco smoking and ionizing radiation exposure [10]. In fact, a Swedish case–control study showed an increased risk of developing basal-like BC, but no other subtypes (OR 4.17, 95% CI: 1.89–9.21) in women with no breastfeeding background versus other nulliparity or breastfeeding individuals [11]. A 20-year follow-up study in 514 women showed that postmenopausal BC patients showing unfavorable lifestyle factors, including obesity, physical inactivity, alcohol use, cigarette smoking or hypertension, had larger tumors than those with no such unfavorable lifestyle factors (26.3 versus 12.3 mm, p = 0.023) [12]. A cohort study showed that BRCA-related mutations are associated with a more aggressive phenotype, leading to a worse BC-related outcome when compared to other BC susceptibility genes such as ATM, CHEK2, STK11, NBN, PTEN, TP53, and PALB2 [13]. Additionally, it has been suggested that viral infections may be associated with BC pathogenesis [14]. In 1936, Bittner discovered a virus, later called the mouse mammary tumor virus (MMTV), in milk coming from an inbred albino breeding mouse with mammary gland carcinoma whose offspring later developed the same tumors [15]. This finding suggested the possibility that a human retrovirus analogue of MMTV could also be related to BC. Furthermore, it was suggested that multiple viral infections may have a role in BC, since some viral sequences were found in human BCs [16]. Of interest, high-risk human papillomavirus (HR-HPV) infections have been proposed as candidates related to BC development [17]. Finally, Epstein–Barr virus (EBV), a very ubiquitous persistent virus, has been detected in BCs, and is associated with this cancer [18,19]. Here, we focus on the epidemiological and experimental evidence which proposes a role of EBV in a subset of BCs.

2. Breast Cancer Classification

BC is a very heterogeneous disease, showing a high phenotypic variability [20,21]. The breast anatomy comprises the glandular tissue where primary BC tumors commonly develop in the lobules (milk-producing glands) or the ducts (milk passages) and the stroma tissue formed by fatty and connective structures [22]. Histologically, BCs are classified into two groups according to the tumor growth pattern. Invasive ductal carcinomas (IDC) and invasive lobular carcinomas (ILC) are the most frequent and aggressive BC types (80% and 10%, respectively), whereas ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) are uncommon types, unable to spread to the adjacent stroma. Furthermore, there are less frequent BC types such as medullary, mucinous (colloid), tubular and inflammatory carcinomas [23]. BCs are hormone-dependent malignancies expressing three receptors in tumors: the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2) [24,25]. Importantly, BC is molecularly classified into four subtypes according to hormone receptor expression and the Ki-67 index into luminal-like (A and B), normal-like, HER-2 enriched and basal-like (triple negative breast cancer, TNBC) carcinomas. [26]. Additionally, the Ki-67 index is a nuclear marker of cell proliferation [26,27]. Luminal A is the most common molecular BC subtype (60%), is characterized by high ER and/or PR levels, is HER-2-negative, and Ki-67 is expressed in <14% of cases. Importantly, these tumors show a low histological grade, and patients have good prognosis. The Luminal B subtype is present in 20% of BC, is characterized by high ER and/or PR levels, is HER-2-negative, and it expresses higher Ki-67 levels (>14%) than the Luminal A subtype. Indeed, these tumors are more likely to have a high histological grade with an aggressive phenotype and low survival rates. The HER-2 subtype represents approximately 20% of BCs. It is important to mention that ER-PR negative tumors express high levels of Ki-67 (>14%). When HER-2 is overexpressed, it contributes to the development and progression of some aggressive BCs. The TNBC subtype accounts for 8–37% of BCs. ER-PR-HER-2 receptors are negative with high levels of Ki-67 (>14%). It is characterized as a highly infiltrating tumor, leading to metastasis with a worse clinical outcome [28]. The hormone receptor status (positive or negative) in BC tumors is considered a prognostic molecular biomarker. Generally, BCs are more likely to be characterized as high grade and show worse prognosis when they are classified as hormonal negative receptors [29]. Additionally, the Ki-67 index is useful as a classifier for Luminal A and Luminal B tumors and as a recurrence-free survival tool in clinical practice [30].

3. Epstein–Barr Virus Structure and Replication Cycle

Epstein–Barr virus (EBV) is an enveloped virus with a linear double-stranded DNA genome of approximately 172 kb in length packed into an icosahedral nucleocapsid. Additionally, the virus harbors a structure called tegument, located between the envelope and the nucleocapsid [31,32,33]. Sequencing-based analysis has led to EBV classification into two types: EBV-1 and EBV-2 [34].
EBV is a well-adapted virus able to persist in human beings for a lifetime through latency establishment in memory B lymphocytes [35]. In fact, approximately 90% of the human population are EBV carriers [36]. EBV infection during early childhood generally is asymptomatic, although when infection occurs during adolescence or early adulthood, individuals can experience symptomatic infectious mononucleosis (IM) [37].
B lymphocytes and epithelial cells are highly susceptible and permissive to EBV infection [38,39]. Additionally, EBV replication involves both a lytic and latent form of infection.
EBV lytic replication occurs in both B lymphocytes and epithelial cells in immunologically competent individuals, while EBV latent infection is assumed to be restricted to B-cells [38,39,40]. In the oropharynx, viral particles have access to Waldeyer´s ring to infect lymphocytes. The viral mayor membrane glycoproteins gp350/220 allow the attachment to the host receptor CR2/CD21 while gp42 allows EBV entry by an endocytosis-mediated mechanism [41,42,43]. The viral genome is transported to the host nucleus where it establishes as a multicopy intranuclear circular episome due to the expression of Epstein–Barr Nuclear Antigen 1 (EBNA-1) with no viral progeny produced [44]. B lymphocytes go through a developing process which originates in four latency programs characterized by the specific expression of EBV latent encoded genes. In naïve B cells, all EBV latent genes from latency III are expressed: EBERs (small non-coding RNA), BARTs (miRNA), EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-LP, LMP-1 (latent membrane protein), LMP-2A, and LMP-2B to transform naïve B cells in lymphoblasts. Next, these cells migrate to the germinal center to accomplish differentiation process where EBERs, BARTs, EBNA-1, LMP-1, LMP-2A, and LMP-2B are expressed (latency II). When memory B cells are proliferating, only EBERs, BARTs and EBNA-1 are expressed (latency I), while resting B memory cells repress viral gene expression to avoid immune recognition (latency 0) [45]. Finally, the last step of B-cell differentiation into plasma cells triggers viral reactivation (switch from latent to lytic infection) with a spread of virions through nasopharyngeal secretions [46] (Figure 1).
In epithelial cells, it is suggested that EBV entry is achieved due to the attachment of the viral gB and the receptor-binding complex gH/gL to the host Ephrin A2 (EphA2) receptor, which allows EBV entry by membrane fusion [47,48]. The viral genome is transported to the host nucleus where EBV finely regulates the expression of lytic genes. EBV lytic activation requires the coordinated expression of two viral immediate-early (IE) proteins: Zta, a leucine zipper DNA-binding protein (also called BZLF1, Zebra or EB1), and Rta protein (also called R) [49,50]. Zebra protein is a transcription factor that interacts with the Z response elements (ZREs) binding sites to activate the transcription of early genes required for viral DNA replication such as BALF5, BBLF4, BSLF1 and BMRF1 [51,52]. The replication complex amplifies the viral genome in a rolling-circle mechanism allowing the genesis of concatemers [53]. After replication, latent genes such as BGLF3, BDLF4, BVLF1, and BDLF3 are expressed to form structural proteins of the nucleocapsid, tegument and surface glycoproteins. These components form the viral particle which, when released to the outer host membrane, cause cell lysis [54].

4. Breast Cancer and EBV Epidemiology

EBV was the first human virus described as oncogenic and classified as carcinogen class I by the International Agency for Research on Cancer (IARC) [55]. Two epithelial tumors have been clearly associated with EBV infection: undifferentiated NPC which harbors EBV in almost 100% of cases and gastric cancer (GC) in almost 10% of cases. [56]. Additionally, EBV is strongly linked to malignancies such as Burkitt’s lymphoma (BL), Hodgkin’s lymphoma (HL), and T-cell lymphoma [57,58,59,60,61].
Interestingly, some lymphocyte-rich types of BC are morphologically similar to NPC [62,63]. There are well-documented publications that have evaluated the presence of EBV infection in BC [18,64,65]. However, the etiological role of EBV in BC is controversial, which may be attributable to different molecular techniques used, the type of clinical specimen, low expression of EBV proteins, and geographic or socioeconomic heterogeneity [66]. In 1995, Labrecque et al. first reported EBV presence in 19/91 (21%) BCs by polymerase chain reaction (PCR). Additionally, EBER-1 was detected in 6/19 (31.5%) BCs by in situ hybridization (ISH). Moreover, a non-statistically significant association with histopathological features was found [18]. Recent studies have also reported that between 30 and 50% of BCs are positive for EBV. Indeed, in 2001 Fina et al. collected 509 IDCs samples and found that 162/509 (31.8%) were EBV-1 positive, with no positive correlation among geographical areas or clinicopathological features [67,68]. In 2001, Chu et al. analyzed 48 BCs by multiple techniques and detected EBER-1 in 5/48 (10%) by ISH, EBNA-1 in 12/48 (25%) cases by IHC but failed to detect LMP-1 and ZEBRA proteins. Furthermore, EBNA-4 and LMP-1 gene fragments were detected by PCR in 7/48 (15%) cases. However, results were not conclusive because only a small subset of tumoral cells was EBER-1 positive and detection of prominent lymphocytic infiltration was only found in 5/7 (71%) PCR-positive cases [69]. In 2005, Kalkan et al. found EBV in 13/57 (23%) of BC tissues by PCR. However, EBV was found in 19/55 (35%) of control samples, suggesting no direct association between EBV and breast carcinogenesis [64]. Another study conducted in 2001 by Preciado et al. found EBV positivity in 12/39 (31%) cases by PCR. In addition, EBNA-1 was detected in 24/69 (35%) BCs by immunohistochemistry (IHC) [65]. Furthermore, in 2009 Joshi et al. detected EBNA-1 expression in 28/51 (54.9%) BC samples from Indian patients by IHC. The seroprevalence determined by EBNA-1 ELISA was higher in BCs (90.9%) than in the control group (81.8%) [70]. In 2010, Lorenzetti et al. evaluated the expression of EBV latent proteins by IHC in 71 BC biopsies classified as IDC and ILC. A higher positivity was observed in LMP-2A expression (16/22, 73%) than EBNA-1 (22/71, 31%), while LMP-1 was not detected. Additionally, EBER transcripts were also detected in 24/71 (31%) tissue samples by ISH [71]. In 2011, Mazouni et al. amplified the BAMH1C viral genomic region, finding 65/169 (33.2%) positive BCs. Furthermore, most EBV-positive tumors were estrogen receptor (ER)-negative, suggesting a more aggressive BC phenotype in those patients [72]. In 2011, Hachana et al. analyzed 123 Tunisian BC specimens and found EBV DNA in 33/123 (27%) cases. Neither EBER detection by ISH nor LMP-1 detection by IHC were positive. In 2011, Aguayo et al. performed the first study in Chile to analyze HPV and EBV infection in 46 BCs. EBNA-1 was found in 6.5% of BC tissues by RT-qPCR and HPV/EBV co-presence was detected only in 3/36 (2.1%) cases. A positive association between EBNA-1 and poor survival was statistically significant (p = 0.013) [73]. In 2012, Zekri et al. established EBV positivity in two Arab groups. The results were 18/40 (45%) and 14/50 (28%), respectively, though EBERs and LMP1 were not detected [74]. In 2013, a study conducted by Khabaz et al. analyzed 92 Jordanian BCs. PCR products for four EBV genes, EBER-2, EBNA-2, BNLF1 and gp220 showed 24/92 (26%) EBV-positive cases. Moreover, IHC for EBNA-1 showed 24/92 (26%) positivity as well. Interestingly, the EBV genome was also evident in 3/49 (36%) non-carcinomatous samples [19]. In 2014, Yahia et al. found LMP-1 and EBNA-4 expression in BCs in 49/92 (53.3%) and 10/92 (11%) cases, respectively. Interestingly, control tissues also harbored EBV genomes in 12/92 (24%) BCs. EBER positive signal was also detected in 18 BC biopsies by ISH. Moreover, methylation frequencies were evaluated reaching 84% in BRCA1 and BRCA2 BC susceptible genes [75]. In 2015, Richardson et al. found 25/70 (34.3%) of EBNA-1 positivity in 70 BCs from New Zealand and 9/70 (13%) in paired normal tissue, although EBV positivity was not associated with grade, receptor status, or disease stage [76]. In 2017, El-nabi et al. analyzed 42 BC specimens by nested PCR and found 12/42 (28.5%) positivity for EBNA-1 [77]. In 2017, Pai et al. found 25/83 (30.1%) EBER expression in primary invasive breast carcinoma (PIBC). A positive correlation between EBER-ISH positivity and clinicopathological features was found. Moreover, most BCs were classified as triple negative (56.5%) suggesting a worse prognosis in those patients [78]. In 2017, Fessahaye et al. analyzed 144 BC biopsies. The PCR for two genomic EBV regions showed presence of 40/144 (27.7%) even though control samples were EBV-negative. EBER signal was also detected in BC specimens by ISH in 5/14 (35.7%) cases and LMP-2A expression was 7/45 (15.5%) cases [79]. In 2019, Sharifpour et al. analyzed 37 BCs by nested PCR where 10/37 (27%) were positive for EBV DNA [80]. In 2020, Mofrad et al. found a 4/59 (6.7%) of EBNA-1 positivity in Iranian samples while all BC control samples were negative. Additionally, EBV-positive tumors were classified as high grade (II, and III) [81] (Table 1).
Conversely, some studies have reported EBV absence in BCs. For instance, in 1998, Chu et al. analyzed 60 invasive BCs from Taiwanese patients and reported that all tissues were negative for EBV non-coding EBER-1, EBER-2 and EBNA-2 and LMP-1 oncoproteins when analyzed by IHC and ISH, respectively [82]. In 1988, Glaser et al. conducted a study on 107 BC samples collected from a diverse population group. The ISH analysis was unable to detect EBER-1 suggesting that EBV detection is geographically restricted to a subset of cases [83]. In 2001, Kijima et al. performed an extensive study in 761 patients clinically diagnosed with cancer. ISH failed to detect EBER in all 61 BC samples from Japanese patients. In 2002, Deshpande et al. analyzed 43 BC tissues and found neither EBERs presence by ISH nor nuclear positivity for EBNA-1, LMP-1 or LMP-2A by IHC, suggesting the absence of latency in BC cells [84]. In 2003, Herrmann et al. conducted a study in 59 BC samples, where only 4/59 (6.8%) were positive by PCR; however, all of these cases were EBERs-negative, suggesting the PCR findings derived from EBV infected lymphocytes detected in the tumor stroma. Additionally, EBNA-1 was not expressed in tumoral cells, concluding that EBV has an indirect role in BC pathogenesis [85]. In 2003, Murray et al. found that BC cells did not harbor EBER when analyzed by ISH. The very low number of EBV copies detected by RT-qPCR 19/92 (21%) did not derive from BCs [86]. Moreover, Perrigoue et al. detected a very low EBV DNA load in 45 BCs. Additionally, EBERs detection by ISH was negative suggesting that previous results reflected basal noise, leading us to conclude that EBV is not related to BC [87]. In 2011, Kadivar et al. failed to detect both EBV genomes by PCR and EBNA-2/LMP-1 by IHC, analyzing 100 BCs [88]. In 2019, Dowran et al. did not detect EBV in 150 BCs from Iran by BHRF1 gene fragment amplification [89] (Table 2).

5. EBV in Breast Cancer: Potential Mechanisms

The molecular mechanisms by which EBV may be involved in BC have not yet been established. However, the molecular characterization of breast tumors has shed some light on potential mechanisms. Thus, as occurs in other epithelial EBV-driven malignancies, EBNA1, LMP1, BZLF1, and BARF1 transcripts have been detected in BC specimens [90], suggesting a role for the corresponding proteins. Additionally, EBV-related tumors displayed a latency II type, characterized by EBNA1 and LMP1-2B expression accompanied by BXLF2 and BFRF3 lytic gene expression, suggesting that latent/lytic switch activation may be involved [91]. EBNA-1 contributes to episomal maintenance allowing the viral genome to tether to the host genome. Interestingly, EBNA-1 contributes to the oncogenic process through multiple mechanisms, including regulation of viral/cellular gene expression and evasion of the immune response (reviewed in [92]). LMP-1 is an oncogenic protein with functions such as the reprogramming of metabolism pathways, promotion of histone and DNA methylation, formation of extracellular vesicles, regulation of antiviral and antitumor immune responses, and promotion of chronic inflammation, among others (reviewed in [93]). BARF1 is an early lytic protein involved in immune evasion as well as contributing to carcinogenesis by promoting cell immortalization and anti-apoptotic effects and increasing cell proliferation (reviewed in [94]).
Hu H et al. demonstrated that EBV infection of immortalized human mammary epithelial cells increased breast tumor formation when these cells were inoculated in NOD/SCID mice. Indeed, the authors concluded that EBV infection predisposes mammary epithelial cells to malignant transformation in cooperation with activated Ras but is no longer required once malignant transformation has occurred, consistent with a “hit and run” mechanism [91]. In line with this finding, in the TCGA database, a higher expression of the EBV epithelial receptor EphA2 was found in normal breast tissues than in BCs, suggesting that normal breast tissues are potentially more susceptible to EBV infection than breast tumors (Figure 2).
It has also been reported that transfection of primate tissue explants with the p31 sub-fragment of EBV DNA results in immortalization of the human breast epithelial cells [96,97], although it remains unknown whether EBV infection occurs before the clonal expansion of breast epithelial cells or if previous DNA alterations are necessary to support latency, as suggested in NPC [98]. Jiun-Han L et al. have reported that HER2/HER3 activation is necessary for EBV-mediated breast cell transformation. Additionally, this effect is mediated by BARF0 expression, although the involved mechanism remains to be elucidated. In fact, BARF0 encodes a protein involved in immune evasion [99].
Yasui et al. (2001) suggested the hypothesis that delayed EBV infections is associated with an increased risk of developing BC [100]. Indeed, other EBV-associated diseases such as Hodgkin’s disease (HD) and multiple sclerosis have been associated with delayed EBV infection, clinically manifested as IM. It has been suggested that immune system overstimulation, which involves a cocktail of cytokine production and inflammation, may be involved in the effect of delayed EBV infection, promoting EBV-associated diseases such as BC.
Interestingly, exosomes released from EBV-infected B cells containing EBV miRNAs or LMP1 cargo can affect adjacent epithelial cells with a potential modulation of tumor behavior and immune evasion [101]. Thus, this possibility warrants more investigation in BC tissues which frequently exhibit tumor-infiltrating lymphocytes (TILs) [102]. Finally, we cannot deny the possibility of cooperation between EBV and other cofactors including xenobiotics and other viruses. For instance, Rajbongshi et al. (2021) reported that both EBV and LMP1 protein increase cell proliferation and induce α9-nAChR upregulation in BC cells. The authors proposed that EBV presence affects the response of BC cells to nicotine [103]. In addition, it has been shown that organophosphate pesticides such as malathion or parathion are related to BC by in vitro and in vivo approaches [104,105,106]. Notably, it was reported that chlorpyrifos, an organophosphate pesticide, can promote EBV lytic cycle activation by promoting BZLF1 expression by oxidative stress in a lymphoblastoid cell line. Considering the relevance of lytic activation in EBV-driven carcinogenesis [107], these issues lead us to speculate about the possibility of cooperation between EBV and pesticides for BC development. In addition, frequent viral coinfection has been detected in BCs including EBV, HPV and MMTV, suggesting the possibility of interactions among viral pathogens [108]. Finally, considering all these findings, a hypothetical model is suggested for EBV-mediated breast carcinogenesis, even though additional studies are necessary to solve this conundrum (Figure 3).

6. Conclusions and Remarks

The role of EBV infection in BC has not yet been established. However, epidemiological studies suggest an increased risk of BC in the presence of EBV. This association appears to be stronger in Asian countries when compared to European countries. Factors related to these differences have not been identified. Additionally, potential mechanisms involved in EBV-mediated breast carcinogenesis have been hypothesized. These mechanisms involve “hit and run” in which EBV infects primary breast cells though after infection the virus is no longer required for cancer progression. The molecular characterization of breast tumors identified viral products including EBNA-1, BZLF1 (Zta protein), BARF-1, BARF-0, BXLF-2, and BFRF-3, which suggest that an abortive lytic cycle may be involved. Additionally, we cannot deny the potential involvement of carcinogenic agents including HPV, MMTV, and xenobiotics (i.e., pesticides) and interactions among them. Additional studies are warranted to identify the mechanisms by which EBV may be related to BC, with a potential impact on prevention or treatment strategies.

Author Contributions

Conceptualization, C.A.-C. and F.A.; writing—original draft preparation, C.A-C.; writing—review and editing, F.A., R.B., G.M.C.; supervision, F.A.; project administration, F.A.; funding acquisition, F.A. and G.M.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by ANID-Fondecyt Grants 1221033 (F.A.) and 1200656 (G.M.C.); ANID-Fondecyt postdoctoral Grant 3190723 (R.B.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

To Brianna Johnson for English grammar revision.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  2. Newman, L.A. Breast Cancer Disparities: Socioeconomic Factors versus Biology. Ann. Surg. Oncol. 2017, 24, 2869–2875. [Google Scholar] [CrossRef] [PubMed]
  3. Igene, H. Global Health Inequalities and Breast Cancer: An Impending Public Health Problem for Developing Countries. Breast J. 2008, 14, 428–434. [Google Scholar] [CrossRef] [PubMed]
  4. Cardoso, F.; Bartlett, J.; Slaets, L.; van Deurzen, C.; van Leeuwen-Stok, E.; Porter, P.; Linderholm, B.; Hedenfalk, I.; Schröder, C.; Martens, J.; et al. Characterization of male breast cancer: Results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. Ann. Oncol. 2017, 29, 405–417. [Google Scholar] [CrossRef]
  5. André, S.; Pereira, T.; Silva, F.; Machado, P.; Vaz, F.; Aparício, M.; Silva, G.L.; Pinto, A.E. Male breast cancer: Specific biological characteristics and survival in a Portuguese cohort. Mol. Clin. Oncol. 2019, 10, 644–654. [Google Scholar] [CrossRef] [Green Version]
  6. Konduri, S.; Singh, M.; Bobustuc, G.; Rovin, R.; Kassam, A. Epidemiology of male breast cancer. Breast 2020, 54, 8–14. [Google Scholar] [CrossRef]
  7. Bray, F.; Jemal, A.; Grey, N.; Ferlay, J.; Forman, D. Global cancer transitions according to the Human Development Index (2008–2030): A population-based study. Lancet Oncol. 2012, 13, 790–801. [Google Scholar] [CrossRef]
  8. Allemani, C.; Matsuda, T.; Di Carlo, V.; Harewood, R.; Matz, M.; Nikšić, M.; Bonaventure, A.; Valkov, M.; Johnson, C.J.; Estève, J.; et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): Analysis of individual records for 37,513,025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 2018, 391, 1023–1075. [Google Scholar] [CrossRef] [Green Version]
  9. Barrios, C.H.; Reinert, T.; Werutsky, G. Global Breast Cancer Research: Moving Forward. Am. Soc. Clin. Oncol. Educ. Book 2018, 38, 441–450. [Google Scholar] [CrossRef]
  10. Akram, M.; Iqbal, M.; Daniyal, M.; Khan, A.U. Awareness and current knowledge of breast cancer. Biol. Res. 2017, 50, 33. [Google Scholar] [CrossRef] [Green Version]
  11. Holm, J.; Eriksson, L.; Ploner, A.; Eriksson, M.; Rantalainen, M.; Li, J.; Hall, P.; Czene, K. Assessment of Breast Cancer Risk Factors Reveals Subtype Heterogeneity. Cancer Res. 2017, 77, 3708–3717. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Lofterød, T.; Frydenberg, H.; Flote, V.; Eggen, A.E.; McTiernan, A.; Mortensen, E.S.; Akslen, L.A.; Reitan, J.B.; Wilsgaard, T.; Thune, I. Exploring the effects of lifestyle on breast cancer risk, age at diagnosis, and survival: The EBBA-Life study. Breast Cancer Res. Treat. 2020, 182, 215–227. [Google Scholar] [CrossRef] [PubMed]
  13. Wang, Y.A.; Jian, J.-W.; Hung, C.-F.; Peng, H.-P.; Yang, C.-F.; Cheng, H.-C.S.; Yang, A.-S. Germline breast cancer susceptibility gene mutations and breast cancer outcomes. BMC Cancer 2018, 18, 315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Gannon, O.; Antonsson, A.; Bennett, I.; Saunders, N. Viral infections and breast cancer—A current perspective. Cancer Lett. 2018, 420, 182–189. [Google Scholar] [CrossRef] [PubMed]
  15. Bittner, J.J. Some possible effects of nursing on the mammary gland tumor incidence in mice. Science 1936, 84, 162. [Google Scholar] [CrossRef]
  16. Lawson, J.S.; Glenn, W.K. Multiple oncogenic viruses are present in human breast tissues before development of virus associated breast cancer. Infect. Agents Cancer 2017, 12, 55. [Google Scholar] [CrossRef]
  17. Blanco, R.; Carrillo-Beltrán, D.; Muñoz, J.P.; Corvalán, A.H.; Calaf, G.M.; Aguayo, F. Human Papillomavirus in Breast Carcinogenesis: A Passenger, a Cofactor, or a Causal Agent? Biology 2021, 10, 804. [Google Scholar] [CrossRef]
  18. Labrecque, L.G.; Barnes, D.M.; Fentiman, I.S.; Griffin, B.E. Epstein-Barr virus in epithelial cell tumors: A breast cancer study. Cancer Res. 1995, 55, 39–45. [Google Scholar]
  19. Khabaz, M.N. Association of Epstein-Barr virus infection and breast carcinoma. Arch. Med. Sci. 2013, 9, 745–751. [Google Scholar] [CrossRef]
  20. Januškevičienė, I.; Petrikaitė, V. Heterogeneity of breast cancer: The importance of interaction between different tumor cell populations. Life Sci. 2019, 239, 117009. [Google Scholar] [CrossRef]
  21. Turashvili, G.; Brogi, E. Tumor Heterogeneity in Breast Cancer. Front. Med. 2017, 4, 227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Morehead, J.R. Anatomy and Embryology of the Breast. Clin. Obstet. Gynecol. 1982, 25, 353–357. [Google Scholar] [CrossRef] [PubMed]
  23. Cserni, G. Histological type and typing of breast carcinomas and the WHO classification changes over time. Pathologica 2020, 112, 25–41. [Google Scholar] [CrossRef]
  24. Cordera, F.; Jordan, V.C. Steroid Receptors and Their Role in the Biology and Control of Breast Cancer Growth. Semin. Oncol. 2006, 33, 631–641. [Google Scholar] [CrossRef] [PubMed]
  25. Clarke, R.B.; Anderson, E.; Howell, A. Steroid receptors in human breast cancer. Trends Endocrinol. Metab. 2004, 15, 316–323. [Google Scholar] [CrossRef]
  26. Perou, C.M.; Sørlie, T.; Eisen, M.B.; Van De Rijn, M.; Jeffrey, S.S.; Rees, C.A.; Pollack, J.R.; Ross, D.T.; Johnsen, H.; Akslen, L.A.; et al. Molecular portraits of human breast tumours. Nature 2000, 406, 747–752. [Google Scholar] [CrossRef]
  27. Hu, Z.; Fan, C.; Oh, D.S.; Marron, J.S.; He, X.; Qaqish, B.F.; Livasy, C.; Carey, L.A.; Reynolds, E.; Dressler, L.; et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genom. 2006, 7, 96. [Google Scholar] [CrossRef] [Green Version]
  28. Yersal, O.; Barutca, S. Biological subtypes of breast cancer: Prognostic and therapeutic implications. World J. Clin. Oncol. 2014, 5, 412–424. [Google Scholar] [CrossRef]
  29. Dunnwald, L.K.; Rossing, M.A.; Li, C.I. Hormone receptor status, tumor characteristics, and prognosis: A prospective cohort of breast cancer patients. Breast Cancer Res. 2007, 9, R6. [Google Scholar] [CrossRef]
  30. Cheang, M.C.U.; Chia, S.K.; Voduc, D.; Gao, D.; Leung, S.; Snider, J.; Watson, M.; Davies, S.; Bernard, P.S.; Parker, J.S.; et al. Ki67 Index, HER2 Status, and Prognosis of Patients with Luminal B Breast Cancer. JNCI J. Natl. Cancer Inst. 2009, 101, 736–750. [Google Scholar] [CrossRef] [Green Version]
  31. Tao, Q.; Young, L.S.; Woodman, C.B.J.; Murray, P.G. Epstein-Barr virus (EBV) and its associated human cancers—Genetics, epigenetics, pathobiology and novel therapeutics. Front. Biosci. 2006, 11, 2672–2713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Lipman, M.; Andrews, L.; Niederman, J.; Miller, G. Direct Visualization of Enveloped Epstein-Barr Herpesvirus in Throat Washing with Leukocyte-Transforming Activity. J. Infect. Dis. 1975, 132, 520–523. [Google Scholar] [CrossRef] [PubMed]
  33. Baer, R.; Bankier, A.T.; Biggin, M.D.; Deininger, P.; Farrell, P.; Gibson, T.J.; Hatfull, G.; Hudson, G.S.; Satchwell, S.C.; Séguin, C.; et al. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature 1984, 310, 207–211. [Google Scholar] [CrossRef] [PubMed]
  34. Sample, J.; Young, L.; Martin, B.; Chatman, T.; Kieff, E.; Rickinson, A. Epstein-Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J. Virol. 1990, 64, 4084–4092. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Miyashita, E.M.; Yang, B.; Babcock, G.J.; Thorley-Lawson, D.A. Identification of the site of Epstein-Barr virus persistence in vivo as a resting B cell. J. Virol. 1997, 71, 4882–4891. [Google Scholar] [CrossRef] [Green Version]
  36. Young, L.; Yap, L.-F.; Murray, P.G. Epstein-Barr virus: More than 50 years old and still providing surprises. Nat. Rev. Cancer 2016, 16, 789–802. [Google Scholar] [CrossRef]
  37. Chan, K.; Tam, J.; Peiris, J.S.M.; Seto, W.; Ng, M. Epstein-Barr virus (EBV) infection in infancy. J. Clin. Virol. 2001, 21, 57–62. [Google Scholar] [CrossRef]
  38. Lemon, S.M.; Hutt, L.M.; Shaw, J.E.; Li, J.-L.H.; Pagano, J.S. Replication of EBV in epithelial cells during infectious mononucleosis. Nature 1977, 268, 268–270. [Google Scholar] [CrossRef]
  39. Sixbey, J.W.; Nedrud, J.G.; Raab-Traub, N.; Hanes, R.A.; Pagano, J.S. Epstein-Barr Virus Replication in Oropharyngeal Epithelial Cells. N. Engl. J. Med. 1984, 310, 1225–1230. [Google Scholar] [CrossRef]
  40. Tierney, R.J.; Steven, N.; Young, L.S.; Rickinson, A.B. Epstein-Barr virus latency in blood mononuclear cells: Analysis of viral gene transcription during primary infection and in the carrier state. J. Virol. 1994, 68, 7374–7385. [Google Scholar] [CrossRef] [Green Version]
  41. Wang, X.; Hutt-Fletcher, L.M. Epstein-Barr Virus Lacking Glycoprotein gp42 Can Bind to B Cells but Is Not Able To Infect. J. Virol. 1998, 72, 158–163. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Fingeroth, J.D.; Weis, J.J.; Tedder, T.F.; Strominger, J.L.; Biro, P.A.; Fearon, D.T. Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc. Natl. Acad. Sci. USA 1984, 81, 4510–4514. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Tanner, J.; Weis, J.; Fearon, D.; Whang, Y.; Kieff, E. Epstein-barr virus gp350/220 binding to the B lymphocyte C3d receptor mediates adsorption, capping, and endocytosis. Cell 1987, 50, 203–213. [Google Scholar] [CrossRef]
  44. Lindahl, T.; Adams, A.; Bjursell, G.; Bornkamm, G.W.; Kaschka-Dierich, C.; Jehn, U. Covalently closed circular duplex DNA of Epstein-Barr virus in a human lymphoid cell line. J. Mol. Biol. 1976, 102, 511–530. [Google Scholar] [CrossRef]
  45. Babcock, G.J.; Hochberg, D.; Thorley-Lawson, D.A. The Expression Pattern of Epstein-Barr Virus Latent Genes In Vivo Is Dependent upon the Differentiation Stage of the Infected B Cell. Immunity 2000, 13, 497–506. [Google Scholar] [CrossRef] [Green Version]
  46. Laichalk, L.L.; Thorley-Lawson, D.A. Terminal Differentiation into Plasma Cells Initiates the Replicative Cycle of Epstein-Barr Virus In Vivo. J. Virol. 2005, 79, 1296–1307. [Google Scholar] [CrossRef] [Green Version]
  47. Zhang, H.; Li, Y.; Wang, H.-B.; Zhang, A.; Chen, M.-L.; Fang, Z.-X.; Dong, X.-D.; Li, S.-B.; Du, Y.; Xiong, D.; et al. Ephrin receptor A2 is an epithelial cell receptor for Epstein-Barr virus entry. Nat. Microbiol. 2018, 3, 164–171. [Google Scholar] [CrossRef]
  48. Miller, N.; Hutt-Fletcher, L.M. Epstein-Barr virus enters B cells and epithelial cells by different routes. J. Virol. 1992, 66, 3409–3414. [Google Scholar] [CrossRef] [Green Version]
  49. Rooney, C.M.; Rowe, D.T.; Ragot, T.; Farrell, P.J. The spliced BZLF1 gene of Epstein-Barr virus (EBV) transactivates an early EBV promoter and induces the virus productive cycle. J. Virol. 1989, 63, 3109–3116. [Google Scholar] [CrossRef] [Green Version]
  50. Ragoczy, T.; Heston, L.; Miller, G. The Epstein-Barr Virus Rta Protein Activates Lytic Cycle Genes and Can Disrupt Latency in B Lymphocytes. J. Virol. 1998, 72, 7978–7984. [Google Scholar] [CrossRef] [Green Version]
  51. Lieberman, P.M.; Hardwick, J.M.; Sample, J.; Hayward, G.S.; Hayward, S.D. The zta transactivator involved in induction of lytic cycle gene expression in Epstein-Barr virus-infected lymphocytes binds to both AP-1 and ZRE sites in target promoter and enhancer regions. J. Virol. 1990, 64, 1143–1155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Fixman, E.D.; Hayward, G.S.; Hayward, S.D. Trans-acting requirements for replication of Epstein-Barr virus ori-Lyt. J. Virol. 1992, 66, 5030–5039. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Hammerschmidt, W.; Sugden, B. Identification and characterization of oriLyt, a lytic origin of DNA replication of Epstein-Barr virus. Cell 1988, 55, 427–433. [Google Scholar] [CrossRef]
  54. Aubry, V.; Mure, F.; Mariamé, B.; Deschamps, T.; Wyrwicz, L.S.; Manet, E.; Gruffat, H. Epstein-Barr Virus Late Gene Transcription Depends on the Assembly of a Virus-Specific Preinitiation Complex. J. Virol. 2014, 88, 12825–12838. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Epstein-Barr Virus and Kaposi’s Sarcoma Herpesvirus/Human Herpesvirus 8. In Proceedings of the IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon, France, 17–24 June, 1997; International Agency for Research on Cancer: Lyon, France, 1997; Volume 70, pp. 1–492. [Google Scholar]
  56. Wong, Y.; Meehan, M.T.; Burrows, S.R.; Doolan, D.L.; Miles, J.J. Estimating the global burden of Epstein-Barr virus-related cancers. J. Cancer Res. Clin. Oncol. 2021, 148, 31–46. [Google Scholar] [CrossRef] [PubMed]
  57. Rowe, M.; Rooney, C.M.; Edwards, C.F.; Lenoir, G.M.; Rickinson, A.B. Epstein-Barr virus status and tumour cell phenotype in sporadic Burkitt’s lymphoma. Int. J. Cancer 1986, 37, 367–373. [Google Scholar] [CrossRef]
  58. Weiss, L.M.; Strickler, J.G.; Warnke, R.A.; Purtilo, D.T.; Sklar, J. Epstein-Barr viral DNA in tissues of Hodgkin’s disease. Am. J. Pathol. 1987, 129, 86–91. [Google Scholar]
  59. Raab-Traub, N.; Flynn, K.; Pagano, J.; Pearson, G.; Huang, A.; Levine, P.; Lanier, A. The differentiated form of nasopharyngeal carcinoma contains epstein-barr virus DNA. Int. J. Cancer 1987, 39, 25–29. [Google Scholar] [CrossRef]
  60. Burke, A.P.; Yen, T.S.; Shekitka, K.M.; Sobin, L.H. Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod. Pathol. 1990, 3, 377–380. [Google Scholar]
  61. Jones, J.F.; Shurin, S.; Abramowsky, C.; Tubbs, R.R.; Sciotto, C.G.; Wahl, R.; Sands, J.; Gottman, D.; Katz, B.Z.; Sklar, J. T-Cell Lymphomas Containing Epstein-Barr Viral DNA in Patients with Chronic Epstein-Barr Virus Infections. N. Engl. J. Med. 1988, 318, 733–741. [Google Scholar] [CrossRef]
  62. Pan, X.; Zhu, X.; Li, Q.Q. Case report of concurrent primary malignancies of the breast and nasopharynx. Oncol. Lett. 2012, 4, 285–288. [Google Scholar] [CrossRef] [PubMed]
  63. Leach, B.I.; Sun, B.; Petrovic, L.; Liu, S.V. Breast metastasis from nasopharyngeal carcinoma: A case report and review of the literature. Oncol. Lett. 2013, 5, 1859–1861. [Google Scholar] [CrossRef] [PubMed]
  64. Kalkan, A.; Ozdarendeli, A.; Bulut, Y.; Yekeler, H.; Cobanoglu, B.; Doymaz, M.Z. Investigation of Epstein-Barr Virus DNA in Formalin-Fixed and Paraffin- Embedded Breast Cancer Tissues. Med. Princ. Pract. 2005, 14, 268–271. [Google Scholar] [CrossRef] [PubMed]
  65. Preciado, M.V.; Chabay, P.A.; De Matteo, E.N.; Gonzalez, P.; Grinstein, S.; Actis, A.; Gass, H.D. Epstein-Barr Virus in Breast Carcinoma in Argentina. Arch. Pathol. Lab. Med. 2005, 129, 377–381. [Google Scholar] [CrossRef] [PubMed]
  66. Glaser, S.L.; Canchola, A.J.; Keegan, T.H.M.; Clarke, C.A.; Longacre, T.A.; Gulley, M.L. 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, 273–287. [Google Scholar] [CrossRef] [PubMed]
  67. Fina, F.; Romain, S.; Ouafik, L.; Palmari, J.; Ben Ayed, F.; Benharkat, S.; Bonnier, P.; Spyratos, F.; Foekens, J.A.; Rose, C.; et al. Frequency and genome load of Epstein-Barr virus in 509 breast cancers from different geographical areas. Br. J. Cancer 2001, 84, 783–790. [Google Scholar] [CrossRef] [Green Version]
  68. Kijima, Y.; Hokita, S.; Takao, S.; Baba, M.; Natsugoe, S.; Yoshinaka, H.; Aridome, K.; Otsuji, T.; Itoh, T.; Tokunaga, M.; et al. Epstein-Barr virus involvement is mainly restricted to lymphoepithelial type of gastric carcinoma among various epithelial neoplasms. J. Med. Virol. 2001, 64, 513–518. [Google Scholar] [CrossRef] [PubMed]
  69. Chu, P.G.; Chang, K.L.; Chen, Y.-Y.; Chen, W.-G.; Weiss, L.M. No Significant Association of Epstein-Barr Virus Infection with Invasive Breast Carcinoma. Am. J. Pathol. 2001, 159, 571–578. [Google Scholar] [CrossRef] [Green Version]
  70. Joshi, D.; Quadri, M.; Gangane, N.; Joshi, R.; Gangane, N. Association of Epstein Barr Virus Infection (EBV) with Breast Cancer in Rural Indian Women. PLoS ONE 2009, 4, e8180. [Google Scholar] [CrossRef] [Green Version]
  71. Lorenzetti, M.A.; De Matteo, E.; Gass, H.; Vazquez, P.M.; Lara, J.; Gonzalez, P.; Preciado, M.V.; Chabay, P.A. Characterization of Epstein Barr Virus Latency Pattern in Argentine Breast Carcinoma. PLoS ONE 2010, 5, e13603. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Mazouni, C.; Fina, F.; Romain, S.; Ouafik, L.; Bonnier, P.; Brandone, J.-M.; Martin, P.-M. Epstein-Barr virus as a marker of biological aggressiveness in breast cancer. Br. J. Cancer 2011, 104, 332–337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Aguayo, F.; Khan, N.; Koriyama, C.; González, C.; Ampuero, S.; Padilla, O.; Solís, L.; Eizuru, Y.; Corvalán, A.; Akiba, S. Human papillomavirus and Epstein-Barr virus infections in breast cancer from chile. Infect. Agents Cancer 2011, 6, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Zekri, A.-R.N.; Bahnassy, A.A.; Mohamed, W.; El-Kassem, F.A.; El-Khalidi, S.J.; Hafez, M.M.; Hassan, Z.K. Epstein-Barr virus and breast cancer: Epidemiological and Molecular study on Egyptian and Iraqi women. J. Egypt. Natl. Cancer Inst. 2012, 24, 123–131. [Google Scholar] [CrossRef] [Green Version]
  75. Yahia, Z.A.; Adam, A.A.; Elgizouli, M.; Hussein, A.; Masri, M.A.; Kamal, M.; Mohamed, H.S.; Alzaki, K.; Elhassan, A.M.; Hamad, K.; et al. Epstein Barr virus: A prime candidate of breast cancer aetiology in Sudanese patients. Infect. Agents Cancer 2014, 9, 9. [Google Scholar] [CrossRef] [Green Version]
  76. Richardson, A.K.; Currie, M.J.; Robinson, B.A.; Morrin, H.; Phung, Y.; Pearson, J.F.; Anderson, T.P.; Potter, J.D.; Walker, L.C. Cytomegalovirus and Epstein-Barr Virus in Breast Cancer. PLoS ONE 2015, 10, e0118989. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. El-Naby, N.E.H.; Mohamed, H.H.; Goda, A.M.; Mohamed, A.E.S. Epstein-Barr virus infection and breast invasive ductal carcinoma in Egyptian women: A single center experience. J. Egypt. Natl. Cancer Inst. 2017, 29, 77–82. [Google Scholar] [CrossRef]
  78. Pai, T.; Gupta, S.; Gurav, M.; Nag, S.; Shet, T.; Patil, A.; Desai, S. 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. [Google Scholar] [CrossRef]
  79. Fessahaye, G.; Elhassan, A.M.; Elamin, E.M.; Adam, A.A.M.; Ghebremedhin, A.; Ibrahim, M.E. Association of Epstein-Barr virus and breast cancer in Eritrea. Infect. Agents Cancer 2017, 12, 62. [Google Scholar] [CrossRef] [Green Version]
  80. Sharifpour, C.; Makvandi, M.; Samarbafzadeh, A.; Talaei-Zadeh, A.; Ranjbari, N.; Nisi, N.; Azaran, A.; Jalilian, S.; Varnaseri, M.; Pirmoradi, R.; 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, 687–692. [Google Scholar] [CrossRef] [Green Version]
  81. Mofrad, M.G.; Kazeminezhad, B.; Faghihloo, E. Prevalence of Epstein-Barr virus (EBV) in Iranian Breast Carcinoma Patients. Asian Pac. J. Cancer Prev. 2020, 21, 133–137. [Google Scholar] [CrossRef] [Green Version]
  82. Chu, J.-S.; Chen, C.-C.; Chang, K.-J. In situ detection of Epstein-Barr virus in breast cancer. Cancer Lett. 1998, 124, 53–57. [Google Scholar] [CrossRef]
  83. Glaser, S.L.; Ambinder, R.F.; DiGiuseppe, J.A.; Horn-Ross, P.L.; Hsu, J.L. Absence of Epstein-Barr virus EBER-1 transcripts in an epidemiologically diverse group of breast cancers. Int. J. Cancer 1998, 75, 555–558. [Google Scholar] [CrossRef]
  84. Deshpande, C.G.; 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. Investig. 2002, 82, 1193–1199. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Herrmann, K.; Niedobitek, G. Lack of evidence for an association of Epstein-Barr virus infection with breast carcinoma. Breast Cancer Res. 2002, 5, R13–R17. [Google Scholar] [CrossRef] [Green Version]
  86. Murray, P.G.; Lissauer, D.; Junying, J.; Davies, G.; Moore, S.; Bell, A.; Timms, J.; Rowlands, D.; McConkey, C.; Reynolds, G.M.; 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, 2338–2343. [Google Scholar]
  87. Perrigoue, J.G.; Boon, J.A.D.; Friedl, A.; Newton, M.A.; Ahlquist, P.; Sugden, B. Lack of Association between EBV and Breast Carcinoma. Cancer Epidemiol. Biomark. Prev. 2005, 14, 809–814. [Google Scholar] [CrossRef] [Green Version]
  88. 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, 489–492. [Google Scholar] [CrossRef]
  89. Dowran, R.; Joharinia, N.; Safaei, A.; Bakhtiyarizadeh, S.; Soleimani, A.A.; Alizadeh, R.; Mir-Shiri, S.; Sarvari, J. No detection of EBV, BKV and JCV in breast cancer tissue samples in Iran. BMC Res. Notes 2019, 12, 171. [Google Scholar] [CrossRef]
  90. Arbach, H.; Viglasky, V.; Lefeu, F.; Guinebretière, J.-M.; Ramirez, V.; Bride, N.; Boualaga, N.; Bauchet, T.; Peyrat, J.-P.; Mathieu, M.-C.; 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, 845–853. [Google Scholar] [CrossRef] [Green Version]
  91. Hu, H.; Luo, M.-L.; Desmedt, C.; Nabavi, S.; Yadegarynia, S.; Hong, A.; Konstantinopoulos, P.A.; Gabrielson, E.; Hines-Boykin, R.; Pihan, G.; et al. Epstein-Barr Virus Infection of Mammary Epithelial Cells Promotes Malignant Transformation. eBioMedicine 2016, 9, 148–160. [Google Scholar] [CrossRef] [Green Version]
  92. Wilson, J.B.; Manet, E.; Gruffat, H.; Busson, P.; Blondel, M.; Fahraeus, R. EBNA1: Oncogenic Activity, Immune Evasion and Biochemical Functions Provide Targets for Novel Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers. Cancers 2018, 10, 109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Wang, L.; Ning, S. New Look of EBV LMP1 Signaling Landscape. Cancers 2021, 13, 5451. [Google Scholar] [CrossRef] [PubMed]
  94. Blanco, R.; Aguayo, F. Role of BamHI-A Rightward Frame 1 in Epstein-Barr Virus-Associated Epithelial Malignancies. Biology 2020, 9, 461. [Google Scholar] [CrossRef] [PubMed]
  95. Goldman, M.; Craft, B.; Hastie, M.; Repečka, K.; McDade, F.; Akhil, K.; Banerjee, A.; Luo, Y.; Rogers, D.; Brooks, A.N.; et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol 2020, 38, 675–678. [Google Scholar] [CrossRef]
  96. Gao, Y.; Lu, Y.-J.; Xue, S.-A.; Chen, H.; Wedderburn, N.; Griffin, B.E. Hypothesis: A novel route for immortalization of epithelial cells by Epstein-Barr virus. Oncogene 2002, 21, 825–835. [Google Scholar] [CrossRef]
  97. Xue, S.A.; Lampert, I.A.; Haldane, J.S.; Bridger, J.E.; Griffin, B.E. Epstein-Barr virus gene expression in human breast cancer: Protagonist or passenger? Br. J. Cancer 2003, 89, 113–119. [Google Scholar] [CrossRef] [Green Version]
  98. Tsao, S.W.; Tsang, C.M.; Pang, P.S.; Zhang, G.; Chen, H.; Lo, K.W. The biology of EBV infection in human epithelial cells. Semin. Cancer Biol. 2012, 22, 137–143. [Google Scholar] [CrossRef]
  99. Aguayo, F.; Castillo, A.; Koriyama, C.; Higashi, M.; Itoh, T.; Capetillo, M.; Shuyama, K.; Corvalan, A.; Eizuru, Y.; Akiba, S. Human papillomavirus-16 is integrated in lung carcinomas: A study in Chile. Br. J. Cancer 2007, 97, 85–91. [Google Scholar] [CrossRef] [PubMed]
  100. Yasui, Y.; Potter, J.; Stanford, J.L.; Rossing, M.A.; Winget, M.D.; Bronner, M.; Daling, J. Breast cancer risk and “delayed” primary Epstein-Barr virus infection. Cancer Epidemiol. Biomark. Prev. 2001, 10, 9–16. [Google Scholar]
  101. Nanbo, A.; Kawanishi, E.; Yoshida, R.; Yoshiyama, H. Exosomes Derived from Epstein-Barr Virus-Infected Cells Are Internalized via Caveola-Dependent Endocytosis and Promote Phenotypic Modulation in Target Cells. J. Virol. 2013, 87, 10334–10347. [Google Scholar] [CrossRef] [Green Version]
  102. Sobral-Leite, M.; Salomon, I.; Opdam, M.; Kruger, D.T.; Beelen, K.J.; Van Der Noort, V.; Van Vlierberghe, R.L.P.; Blok, E.J.; Giardiello, D.; Sanders, J.; et al. Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes. Breast Cancer Res. 2019, 21, 90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Rajbongshi, L.; Noh, M.H.; Kim, Y.S.; Hur, D.Y. Effects of Epstein-Barr Virus Infection on the Response of Human Breast Cancer Cells to Nicotine. Anticancer Res. 2021, 41, 3449–3458. [Google Scholar] [CrossRef] [PubMed]
  104. Calaf, G.M.; Bleak, T.C.; Roy, D. Signs of carcinogenicity induced by parathion, malathion, and estrogen in human breast epithelial cells (Review). Oncol. Rep. 2021, 45, 24. [Google Scholar] [CrossRef] [PubMed]
  105. Calaf, G.M.; Bleak, T.C.; Muñoz, J.P.; Aguayo, F. Markers of epithelial-mesenchymal transition in an experimental breast cancer model induced by organophosphorous pesticides and estrogen (Review). Oncol. Lett. 2020, 20, 84. [Google Scholar] [CrossRef] [PubMed]
  106. Yang, K.J.; Lee, J.; Park, H.L. Organophosphate Pesticide Exposure and Breast Cancer Risk: A Rapid Review of Human, Animal, and Cell-Based Studies. Int. J. Environ. Res. Public Health 2020, 17, 5030. [Google Scholar] [CrossRef]
  107. Morales-Sánchez, A.; Fuentes-Panana, E.M. The Immunomodulatory Capacity of an Epstein-Barr Virus Abortive Lytic Cycle: Potential Contribution to Viral Tumorigenesis. Cancers 2018, 10, 98. [Google Scholar] [CrossRef] [Green Version]
  108. Gupta, I.; Ulamec, M.; Peric-Balja, M.; Ramic, S.; Al Moustafa, A.-E.; Vranic, S.; Al-Farsi, H.F. Presence of high-risk HPVs, EBV, and MMTV in human triple-negative breast cancer. Hum. Vaccines Immunother. 2021, 17, 4457–4466. [Google Scholar] [CrossRef]
Figure 1. Model of primary infection by Epstein–Barr virus in the oropharynx.
Figure 1. Model of primary infection by Epstein–Barr virus in the oropharynx.
Biology 11 00799 g001
Figure 2. EphA2 transcripts in primary breast tumors, metastatic, and normal breast tissues (TCGA, n = 1284; p = 0.000, One-way ANOVA). Raw data were extracted from University of California, Santa Cruz (xena.ucsc.edu). UCSC Xena functional genomics explorer (https://xenabrowser.net accessed on 1 February 2022) [95].
Figure 2. EphA2 transcripts in primary breast tumors, metastatic, and normal breast tissues (TCGA, n = 1284; p = 0.000, One-way ANOVA). Raw data were extracted from University of California, Santa Cruz (xena.ucsc.edu). UCSC Xena functional genomics explorer (https://xenabrowser.net accessed on 1 February 2022) [95].
Biology 11 00799 g002
Figure 3. A hypothetical model of EBV role in breast carcinogenesis. Primary breast epithelial cells are susceptible to EBV infection, probably using EphA2 receptor. Once EBV latency is established, including EBNA-1, EBER and BART expression, the lytic switch can be activated. Xenobiotics may be involved in Zp activation as suggested in some models. BARF0 is involved in Her2/Her3 activation promoting tumor transformation by Ras/Raf/MEK/Erk and Pi3K/akt signaling pathways. BARF1 is involved in immune evasion and providing tumor properties. Xenobiotics or additional viral infections can cooperate with EBV for increasing breast tumor properties.
Figure 3. A hypothetical model of EBV role in breast carcinogenesis. Primary breast epithelial cells are susceptible to EBV infection, probably using EphA2 receptor. Once EBV latency is established, including EBNA-1, EBER and BART expression, the lytic switch can be activated. Xenobiotics may be involved in Zp activation as suggested in some models. BARF0 is involved in Her2/Her3 activation promoting tumor transformation by Ras/Raf/MEK/Erk and Pi3K/akt signaling pathways. BARF1 is involved in immune evasion and providing tumor properties. Xenobiotics or additional viral infections can cooperate with EBV for increasing breast tumor properties.
Biology 11 00799 g003
Table 1. Epstein–Barr virus presence in breast cancer worldwide.
Table 1. Epstein–Barr virus presence in breast cancer worldwide.
Author/YearBC TypeEBV DetectionDetection Method
Labrecque
1995
IDC-DCIS
BD/L-ILC
MC-T/C
19/91 (21%)PCR
SB
ISH
Fina
2001
IDC162/509 (31.8%)PCR
SB
ISH
RT-qPCR
Chu
2001
IDC
ILC
195/48 (10%)ISH
Kalkan
2005
IDC-ILC
NEC
13/57 (23%)PCR
Preciado
2005
DC-LCI
PC-AC
24/69 (35%)PCR
SB
IHC
Joshi
2009
IDC-ILC
NEC
28/51 (54.9%)ELISA
IHC
Lorenzetti
2010
IDC-ILC22/71 (31%)PCR
IHC
ISH
Mazouni
2011
IDC-ILC65/196 (33.2%)RT-qPCR
Hachana
2011
IDC-ILC
MC
33/123 (27%)PCR
ISH
IHC
Aguayo
2011
IDC-ILC
CC
3/46 (6.5%)RT-qPCR
ISH
IHC
Zekri
2012
IDC-ILC18/40 (45%)
14/50 (28%)
PCR
ISH
IHC
Khabaz
2013
IDC-ILC
MC-CC
24/92 (26%)PCR
IHC
Yahia
2014
IDC-ILC
CIS
49/92 (53%)PCR
ISH
Richardson
2015
IDC25/70 (34.3%)qPCR
El-Nabi
2017
IDC12/42 (28.5%)Nested PCR
IHC
Pai
2017
IDC-MPC
ILC
25/83 (30.1%)ISH
Fessahaye
2017
IDC-LC
MC-NEC
40/144 (27.7%)PCR
ISH
IHC
Sharifpour
2019
DC10/37 (27%)Nested PCR
IHC
Mofrad
2020
IDC-ILC4/59 (6.7%)PCR
IDC, invasive ductal carcinoma; DCIS, ductal carcinoma in situ; BD/L, borderline ductal/lobular; ILC, invasive lobular carcinoma; MC, medullary carcinoma; CC, colloid carcinoma; T/C, tubular-cribriform; NEC, non-specified carcinomas; LCI, lobular carcinoma in situ; PC, papillary carcinoma; AC, adenocystic carcinoma; CIS, carcinoma in situ; MPC, metaplastic carcinoma; LC, lobular carcinoma; DC, ductal carcinoma; PCR, conventional polymerase chain reaction; SB, Southern blot; ISH, in situ hybridization; IHC, immunohistochemistry.
Table 2. Epstein–Barr virus absence in breast cancer worldwide.
Table 2. Epstein–Barr virus absence in breast cancer worldwide.
Author/YearBC TypeEBV DetectionDetection Method
Chu
1998
IDC-ILC0/60 (0%)IHC
ISH
Glaser
1998
BCs0/107 (0%)ISH
Kijima
2001
ADC0/61 (0%)ISH
Deshpande
2002
DC
LC
0/43 (0%)ISH
IHC
Herrmann
2003
IDC-ILC
MC
NEC
0/59 (0%)ISH
IHC
PCR
Murray
2003
DCIS-MC
CC
0/98 (0%)RT-qPCR
ISH
IHC
Perrigoue
2005
IDC-ILC
TC-CC
0/45 (0%)RT-qPCR
ISH
Kadivar
2011
IDC-ILC
AC-CRC
PC-CC
0/100 (0%)PCR
IHC
Dowran
2019
DC-LC
IDC-ILC
0/150 (0%)PCR
IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; BCs, breast carcinomas; ADC, a-denocarcinoma; DC, ductal carcinoma; LC, lobular carcinoma; MC, medullary carcinoma; NEC, non-specified carcinomas; DCIS, ductal carcinoma in situ; CC, colloid carcinoma; TC, tubular carcinoma; AC, apocrine carcinoma; CRC, cribriform carcinoma; PC, papillary carcinoma.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Arias-Calvachi, C.; Blanco, R.; Calaf, G.M.; Aguayo, F. Epstein–Barr Virus Association with Breast Cancer: Evidence and Perspectives. Biology 2022, 11, 799. https://0-doi-org.brum.beds.ac.uk/10.3390/biology11060799

AMA Style

Arias-Calvachi C, Blanco R, Calaf GM, Aguayo F. Epstein–Barr Virus Association with Breast Cancer: Evidence and Perspectives. Biology. 2022; 11(6):799. https://0-doi-org.brum.beds.ac.uk/10.3390/biology11060799

Chicago/Turabian Style

Arias-Calvachi, Claudia, Rancés Blanco, Gloria M. Calaf, and Francisco Aguayo. 2022. "Epstein–Barr Virus Association with Breast Cancer: Evidence and Perspectives" Biology 11, no. 6: 799. https://0-doi-org.brum.beds.ac.uk/10.3390/biology11060799

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop