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Investigation of human JC and BK polyomaviruses in breast carcinomas
Mohamed Hachana • Khaled Amara Sonia Ziadi • Riadh Ben Gacem • Sadok Korbi • Mounir Trimeche
Received: 16 February 2011 / Accepted: 4 November 2011 / Published online: 23 November 2011 Ó Springer Science+Business Media, LLC. 2011
Abstract We have previously showed the presence of the simian virus 40 (SV40) and the mouse mammary tumor virus (MMTV)-like in a signiﬁcant proportions of Tunisian breast carcinomas. However, to date there are no published studies concerning evaluation of the possible implication of the human polyomaviruses JC (JCV) and BK (BKV) in breast carcinomas. The presence of JCV and BKV DNA was investigated by PCR in a 123 primary breast carcinomas and matched adjacent non-tumor breast tissues. The results were correlated to clinicopathological and virological parameters. JCV T-antigen DNA was detected in 23% of breast carcinoma cases; however, all cases were negative for BKV. JCV T antigen PCR products were further conﬁrmed as authentic JCV genome by direct sequencing. JCV was found in invasive ductal carcinomas (28/112 cases) but not in invasive lobular carcinomas (0/5) or medullary carcinomas (0/6). JCV DNA presence correlates inversely with the expression of estrogen (P = 0.022) and progesterone (P = 0.008) receptors. JCV DNA presence correlates also with ‘‘triple negative’’ phenotype (P = 0.021). With regard to virological data, a trend toward an inverse correlation was noted between the presence of JCV and SV40 (P = 0.06). Moreover, signiﬁcant correlation was found between multiple viral infection (JCV, and/or SV40, and/or MMTV-like in the same tumor) and ‘‘triple negative’’ phenotype (P = 0.001) and also with p53 accumulation (P = 0.028). To the best of our knowledge, this is the ﬁrst study demonstrating the presence of JCV in a subset of breast carcinomas. Also our results suggest that
M. Hachana (&) Á K. Amara Á S. Ziadi Á R. B. Gacem Á S. Korbi Á M. Trimeche Department of Pathology, Farhat Hached Hospital, 4000 Sousse, Tunisia e-mail: email@example.com
‘‘triple negative’’ breast carcinomas are viral-related tumors. Keywords Breast cancer Á Polyomaviruses Á BK virus Á JC virus Á Tunisia
Introduction Breast carcinoma is a very common malignancy in women and it is well recognized as a heterogeneous condition and a major cause of death among women [32, 41]. There is a general agreement that inherited and genetic factors inﬂuence breast cancer development, however, the potential role of other environmental contributors remains unclear. Although there are recognized factors that increase the risk of breast cancer, the etiology of this cancer remains largely unknown. The human polyomaviruses JC (JCV) and BK (BKV) are oncogenic in animal models and readily transform animal and human cells in vitro . A major mechanism by which this is achieved is through the action of the transforming proteins of the early region. In particular, the large T-antigen act as a transcription factor and interacts with several cellular proteins, including the 2 tumor suppressor proteins, pRb and p53, key players in cell cycle progression . Infection with JCV and BKV is prevalent in the human population, although its mode of transmission is not clear [2, 3, 19]. BKV and JCV establish subclinical infections in immunocompetent hosts, but can produce pathologic effects in immunocompromised individuals by destroying infected cells . Genomic sequences of these two viruses have been reported in different human tumor types. Indeed, several
which amplify a 173 bp sequence in the NH2-terminal region of the JCV T antigen. BKV has been detected in different human tumors including Kaposi’s sarcoma. a total of 123 Tunisian patients with sporadic breast carcinomas were randomly selected from the tumor’s bank retained by the Department of pathology at the Farhat-Hached Hospital in Sousse. DNA direct sequencing for PCR products PCR products were also sequenced to conﬁrm their identity. Marnes-laCoquette. The aim of our present study was to evaluate the possible implication of JCV and BKV in breast carcinogenesis. According to the WHO Classiﬁcation . and JCV polyomaviruses . Extracted DNAs were assessed for their suitability for PCR analysis by a control reaction designed to amplify a fragment of 268 bp of the b-globin gene as described previously .2 lM of each sense and antisense primers. glioblastomas. for 1 min at the speciﬁc annealing temperature (56 and 57°C. and the primers set BES-3 (50 -AATATTATGCCCAGCACACATG-30 ) and BES-6 (50 -CTTTCCCTCTGATCTACACCAG-30 ). France).  was used. the histopathological type was ductal in 112 cases. Baylor College of Medicine. and for 1 min at 72°C. oligoastrocytomas. and p53 expression of these cases was reported in our previous report . Tunisia. 27. Survival data were available for 84 patients. The clinical staging was done by the TNM staging system  and the malignancy stage of the inﬁltrating carcinomas was scored according to the modiﬁed Scarff–Bloom–Richardson (SBR) classiﬁcation . DNA extraction. 35]. PCR.4). and p53. 10 mM Tris–HCl (pH 8. and medullary in 6 cases. 9. The reaction was ﬁnished with a 5 min extension at 72°C. we examined the presence of these viruses in a series of 123 cases of human breast carcinomas using polymerase chain reaction (PCR). Madison.970 Breast Cancer Res Treat (2012) 133:969–977 studies have demonstrated that JCV was found in a large percentage of brain tumors.1 cycle sequencing kit on an ABI PRISM 3100Ò Avant Genetic Analyzer (Applied Biosystems). All cases were selected on the basis of availability of paired frozen samples of breast cancer tissue and matched adjacent normal breast tissue obtained at the time of primary surgery before any treatment. PCR products were analyzed by electrophoresis on 2% agarose gels containing ethidium bromide. respectively for JCV and BKV). and 1 U of Taq DNA TM polymerase (Promega. Vilchez. The PCR reactions were performed using 200 ng of DNA template in a total volume of 25 ll. 16]. The cases were diagnosed between 1995 and 2006. Furthermore. to rule out a possible contamination of our samples by plasmids containing JCV and/or BKV sequences. Watertown. The clinicopathological characteristics and immunohistochemical status of estrogen and progesterone receptors. USA). Positive controls for PCR reactions were plasmids containing cloned JCV (pBRJC-MAD-1) and BKV (pBRBKVDunlop) genomes (kindly provided by Dr. lobular in 5 cases. 200 mM of each dNTP. The presence of JCV and BKV was analyzed by PCR using the primers set PEP1 (50 -AGTCTTTAGGGTCTTC TACC-30 ) and PEP2 (50 -GGTGCCAACCTATGGAA CAG-30 ). 50 mM KCl. which amplify a 151 bp sequence in the DNA binding region of the BKV T antigen [4. Standard precautions were taken to guard against PCR contamination. and ependymomas [5. Houston. In addition. BK virus. Cycling conditions were as follows: denaturation at 95°C for 5 min. Materials and methods Patients and samples For this study. Texas. 1. 30]. Negative controls were genomic DNA extracted from normal breast tissues. 11] and more recently in gastric cancers [28. brain tumors. 24. 36]. PCR experiments for each case were repeated 4 times. pBRBKV-Dunlop and in virtually all plasmids that are propagated in Escherichia coli. For this issue. in fact there is some sequence similarity between SV40. such as astrocytomas. USA) in a PTC 200 DNA engine thermal cycler (MJ Research. HER2. PCR DNA was extracted from frozen tissues according to protocol described in our previous study . 1. a primer pair (50 -GCTCACGCTGTAGGTATCTC-30 and 50 -TCTAGTGTAGCCGTAGTTAG-30 ) previously described by Carbone et al. in colorectal cancers [5. containing 0.5 mM MgCl2. Samples were considered to contain viral DNA if they exhibited detectable signals at least three times under ethidium bromide staining conditions. 11. We also investigated the relationship between these viruses and several clinicopathological data. and gel electrophoresis were performed in a separate room in the laboratories. Regis A. All steps of the PCR procedure were conducted in parallel with positive and negative controls. immunohistochemical expression status of progesterone and estrogen receptors. The electrophoretic pattern was photographed under ultraviolet light with the Gel Doc 2000 System (Bio-Rad. USA). All positive PCR products were puriﬁed from agarose gels using Wizard SV Gel and PCR Clean-Up Puriﬁcation kit (Promega) and sequenced using an ABI PRISM BigDyeÒ Terminator v. followed by 35 cycles of 1 min at 95°C. HER2. Similarly. 123 . This primer pair ampliﬁes a 241 bp portion of the pUC origin of replication present in pBRJC-MAD-1. and urinary tract tumors [8.
2). indicating the absence of JCV DNA sequence in these cases. none of the breast carcinoma tissue samples examined yielded a PCR product which indicated the presence of BKV DNA (Fig. 1b). 12. Each case was analyzed for the presence of JCV and BKV. and SV40 sequences (GenBank Accession Nos. Statistical analysis Relationships between the presence of these viruses and clinicopathological parameters. HER2-) breast carcinomas (P = 0. All samples showed adequate DNA quality for further DNA ampliﬁcation procedures (Fig. NC_001538).Breast Cancer Res Treat (2012) 133:969–977 971 All the sequencing data obtained were analyzed for homology using the nucleotide–nucleotide ‘‘BLAST’’ search feature located on the National Center for Biotechnology Information Web site. To check for plasmid contaminations and eliminate the possibility of false-positive. Whereas. Immunohistochemical overexpression of HER2 and accumulation of p53 did not vary signiﬁcantly between JCV-positive and -negative cases.05 were regarded as statistically signiﬁcant. 3). or tumor size. lanes B represent negative control Direct DNA sequencing for PCR products Results Viral detection The quality of extracted DNA was assessed by performing b-globin DNA PCR. Cases 3 and 39 lack bands in both tumor and normal breast tissues. probability values of P \ 0. JCV presence correlates inversely with the expression of estrogen (P = 0. 1 Representative ethidium bromide-stained agarose gel electrophoresis after speciﬁc PCR of a b-globin gene. occurrence of contralateral breast cancer or second primary tumor or death without relapse. With regard to hormonal receptors. none of the adjacent non-tumor breast tissue samples was positive for these viruses (Fig. Surviving patients were censored at the day of the last contact. b human polyomavirus JC (JCV) and c human polyomavirus BK (BKV). This analysis showed that all breast DNA samples were negative and only the positive control (plasmid pBRJC-MAD-1) showed positive signal (Fig.83) programs. 1b). We also noted a signiﬁcant correlation between JCV presence and ‘‘triple negative’’ (ER-. lymph node status. For all of the tests. immunohistochemical ﬁndings were evaluated by the v2 test or Fisher’s exact test as appropriate. PR-. 123 . BKV (GenBank Accession Nos. AY538779) using BLAST and ClustalW (version 1. PCR products were identiﬁed as authentic amplicons of the JCV (and not the BKV or SV40 species of polyomavirus) genome by DNA sequencing. all JCV-positive breast samples were tested by PCR using an additional primer set that ampliﬁes a 241 bp sequence of the pUC origin of replication present in pBRJC-MAD-1. Clinicopathological correlations The comparison of the clinicopathological and immunohistochemical data between the JCV-positive and -negative breast cancer cases is summarized in Table 1. Appropriate primers were used to amplify a band that had an appropriate size compared to the positive controls. 1a). IL. distant relapse. histological grade. Overall survival was measured from the day of randomization until death due to any cause. Disease.022) and progesterone (P = 0.008) receptors. Furthermore. Fig. NC_001699). however. and 161 show positivity in tumor (T) but not in normal (N) breast tissues. Overall. Lanes M show 50 bp ladder (Promega). In contrast.free survival was measured from randomization until local recurrence. JCV DNA was found in 23% (28/123) of these cases (Fig. Cases 97. 1c). Although there were several point mismatches no signiﬁcant differences in the DNA sequences were observed between examined breast carcinoma cases (Fig. histological type. lanes P represent positive controls. All analyses were carried out using the SPSS software package (Chicago. whichever occurred ﬁrst.021). Times to event distributions were estimated using Kaplan–Meier curves. no correlation was found between the detection of JCV and patient’s age. USA). these data were aligned with JCV (GenBank Accession Nos.
All JCV-positive (lanes 36.) with JCV sequences retrieved from GenBank database (Accession Nos. No signiﬁcant differences in overall or disease-free survival rates were seen between patients according to the JCV positivity and negativity. and 161) cases showed negative results. coli. 163. NC_001699).83 Survival data were available for 83 patients with a median follow-up period of 59 months. 123 . and only the positive control (plasmid pBRJC-MAD-1) showed positive signal (lane T) Fig. Lanes MW shows 50 bp DNA ladder. lane B represents negative control. Overall and disease-free survival were compared between JCV PCR-positive and -negative cases (Fig. 12. 2 Ethidium bromide-stained agarose gel showing representative examples of PCR experiment using a set of primers amplifying a 241 bp fragment of the pUC origin of replication present in pBRJCMAD-1 and in virtually all plasmids that are propagated in E. Sequences were aligned and then manually adjusted using CLUSTAL W. This experiment was used to investigate a possible contamination of our DNA breast carcinomas samples by JCV genome present in the pBRJC-MAD-1 plasmid. which ranged from 4 to 143 months. 4). 69. 97.972 Breast Cancer Res Treat (2012) 133:969–977 Fig. 3 Multiple nucleotide alignment of the JCV T antigen sequences from ten Tunisian human breast carcinomas (indicated by their respective Nos. version 1.
These viruses remain in a latent stage throughout life and can reactivate under immunosuppressive conditions inducing multifocal leukoencephalopathy for JCV and nephropathy.579 4 15 9 28 0 0 5 10 13 4 26 20 6 14 14 21 7 21 7 20 8 16 12 26 2 24 4 11 43 41 0. HER2-) (P = 0. for BKV [2. BKV was not detected in any breast cancer cases. and ‘‘triple negative’’ phenotype (ER-. and also with p53 accumulation (P = 0.021 simian virus 40 (SV40) and the mouse mammary tumor virus (MMTV)-like . BKV sequences have been reported to be present in different human tumors including Kaposi’s sarcoma. exclusively in the tumor tissues.Breast Cancer Res Treat (2012) 133:969–977 Table 1 Correlation between the presence of JCV DNA and clinicopathological characteristics of breast carcinomas Number of JCV-positive cases Age (years) \35 35–50 [50 Histological type Invasive ductal carcinomas Invasive lobular carcinomas Medullary carcinomas Histological gradeb Grade I Grade II Grade III Tumor size (mm) B20 [20 Lymph node metastasesc Negative Positive p53d Negative Positive Estrogen receptord Negative Positive Progesterone receptord Negative Positive HER2d Negative Positive Triple negativee No Yes Simian virus 40 (SV40) Negative Positive MMTV-like Negative Positive a 973 Number of JCV-negative cases P valuea 0. respectively.522 54 41 0. to our knowledge. bold numbers indicate signiﬁcant correlations b Scarff-Bloom and Richardson classiﬁcation was performed only in invasive ductal carcinoma cases c d e Twenty cases did not beneﬁt from the lymph nodes resection Immunohistochemical data were reported previously  Simultaneous negativity for estrogen and progesterone receptors.169 84 5 6 0. 3. colon cancers [14.805 61 16 0. Table 1). Recently. Likewise. with and without viral infection is summarized in Table 2.235 19 33 32 0. 28]. JCV T antigen DNA sequences were detected by PCR in 23% of cases. and tumors of the urinary tract [8. to rule out a possible contamination of our breast samples by P-values were calculated by v2 or Fisher’s exact tests (two-sided) and were considered to be statistically signiﬁcant for P \ 0.001). SV40 and MMTV-like infection in ﬁve cases. brain tumors. links have been suggested between JCV and various types of human cancers.05. ampliﬁcation and analyse of PCR products by electrophoresis were performed in different areas. Indeed. deﬁned by the presence of more than one viral agent in the same tumor. In our study. 5). For this issue we evaluated the prevalence of JCV and BKV in Tunisian patients with breast carcinomas and we analyzed their relations to clinicopathological features. and/or SV40. JCV and MMTV-like infection in three cases. In our experiments. 16]. In contrast. 9. and/or MMTV-like) in the same tumor. this ﬁnding indicates that BKV is unlikely to play a role in the breast carcinogenesis. In addition. and only one patient was infected with the three viruses simultaneously (Fig. We found a trend toward an inverse correlation between the presence of JCV and SV40 in breast carcinomas (P = 0. The comparison of the clinicopathological characteristics between the two groups of breast carcinomas. esophageal cancers . PR-.312 22 73 0. 35]. However. with a large portion of people (60–80%) exhibiting speciﬁc antibodies.06 0. the 123 . 25.008 44 51 0. simultaneous multiple viral infections. This analysis revealed a signiﬁcant correlation between viral infection deﬁned by the presence of one or more viruses (JCV. such as brain tumors . to date no study has been conducted to investigate the presence of JCV and BKV in breast carcinomas. gastric cancers [28. and HER2 We also assessed the relation between JCV and two others viruses also found positives previously in some breast carcinoma cases in the same Tunisian series. and lung cancers [1. PCR contamination is improbable since DNA extraction. Moreover. 38]. negative control was included in every reaction and no ampliﬁcation was shown. Discussion JCV and BKV are two human polyomaviruses widespread among general population. were noted in 10 breast carcinoma cases.022 48 47 0.028). simultaneous JCV and SV40 infection was noted in two cases. 19].06.726 71 24 75 20 73 22 82 13 1 0. Moreover.
This experiment rules out the possibility that our JCV-positive breast samples may be caused by plasmid contamination. the SV40 and the MMTV-like in a series of 123 breast carcinoma cases from Tunisia plasmids containing JCV sequences. 5 A diagram summarizing the distribution of the number of positive cases for the JCV. lymph node metastasis. We found a trend toward an inverse correlation between the presence of JCV and SV40 in breast carcinomas (see Table 1). we also assessed the relation between JCV and two others viruses (SV40 and MMTVlike) also found positive previously in the same series of Tunisian breast carcinomas studies. 18. However. In contrast. Interestingly. we detected a simultaneous 123 . tumor size. Furthermore. Additional attention should be devoted to the breast carcinoma histological type in future studies exploring more important number of cases and histological types to determine whether JCV is speciﬁcally associated with the invasive breast ductal carcinoma type. all our breast samples were tested by PCR assay amplifying DNA sequence present in common laboratory plasmids. . Similar correlation was also reported for other viruses that have been related to breast cancer. histological type and grade. 31. it is interesting to note that all the 28 JCV-positive breast carcinoma cases belong to the invasive breast ductal carcinoma type and none of the six medullary carcinomas or the ﬁve invasive lobular carcinomas was positive (see Table 1). 26. such as Epstein-Barr virus (EBV)  and the MMTV like .974 Fig. no signiﬁcant correlation was found between JCV and the other clinicopathological parameters examined. To our knowledge. and survival rates. These observations should stimulate further investigations on the association of this oncogenic virus in other human populations and the investigation of pathways that may be deregulated by JCV in the tumor cells. This analysis showed that all breast samples were negative.008) receptors. 29. and has been reported that JCV T antigen bind and inactivate wild type of p53 [26. Additional studies looking at JCV are needed to clarify the genetic or the epigenetic mechanisms by which JCV interferes with the hormonal receptors expression in breast carcinomas. This result indicates that the two polyomavirus JCV and SV40 are independent factors in breast carcinogenesis. 15. In the current study. In the current study. direct sequencing of the PCR products reveled that the ampliﬁed DNA sequences found in the breast specimens were authentically of JCV and not of related viruses genome. the JCV interacts preferentially with other pathways than p53. this is the ﬁrst demonstration of the presence of JCV DNA in breast cancer s. HER2 overexpression. 14. 29] and cause chromosomal instability [18. as well as the stabilization of b-catenin [14. 4 Kaplan-Meier estimates of overall survival (a) and disease-free survival (b) of breast carcinomas patients classiﬁed according to the status of JCV Breast Cancer Res Treat (2012) 133:969–977 Fig. 35]. 17. including patient’s age. we found a correlation between the presence of JCV and the negativity of expression of estrogen (P = 0. Nevertheless. in our study we do not ﬁnd a signiﬁcant correlation between the presence of JCV and aberrant accumulation of p53. 17]. This negative result could be due to the number of investigated cases or it could indicate that in the breast. 29. in our breast carcinoma series. These ﬁndings suggest the absence of a speciﬁc proﬁle for JCV-related breast carcinomas. 23.022) and progesterone (P = 0. Previous studies have suggested the link between JCV and various types of human cancers [10. The presence of the JCV DNA in breast tumors but not in the adjacent normal breast tissues suggests a role of this virus in breast carcinogenesis. 31].
De Marco MA. with and without viral infection (one or more viruses in the same tumor). Ryschkewitsch CF. Agostini HT. viralrelated cancers. de la Recherche Scientiﬁque et Technoll’Enseignement Supe ` re de la Sante ´ Publique’’ of Tunisia.64 2.003 35 23 34 31 0. Takahashi H. bold numbers indicate signiﬁcant correlations b a Scarff-Bloom and Richardson classiﬁcation was performed only in invasive ductal carcinoma cases Twenty cases did not beneﬁt from the lymph nodes resection Immunohistochemical data were reported previously  c d e Simutaneous negativity for estrogen receptors.0000213126. Kutsuna T.001 0.042 8 24 26 7 34 24 0. and HER2 multiple viral infection in 10 breast carcinoma cases (see Fig. J Natl Cancer Inst 91:1376–1381 7. J Clin Microbiol 27:1174–1179 5. Bocchetta M. Ryschkewitsch CF.CAN-05-1911 Deﬁned by the presence of one or more viruses (JC virus. Interestingly. progesterone receptors. ogie’’ and the ‘‘Ministe Conﬂict of interest The authors have no conﬂicts of interest in relation to this article. Brubaker GR. these infectious agents. indicating a possible interaction of these viruses as cofactors in breast carcinogenesis. Benhamou E.370 26 32 42 23 0. This observation is also very interesting in the future for the therapeutic management of this group of ‘‘triple negative’’ breast carcinomas for which hormonal therapy and anti-HER2 immunotherapy are not possible.96590. Pass HI (2005) SV40 detection in human tumor specimens. Murata S. These ﬁndings suggest a role of JCV in breast carcinogenesis.1097/01. Dagostin S.036 39 19 26 39 0.05. We also demonstrated a correlation between JCV presence and the absence of hormonal receptors expression. Takano Y (2007) Detection of the JC virus genome in lung cancers: possible role of the T-antigen in lung oncogenesis. Blattner WA. at least in part. Girones R (2001) Excretion and transmission of JCV in human populations.1158/0008-5472. Indeed. Boﬁll-Mas S. Shah KV (1989) Detection of BK virus and JC virus in urine and brain tissue by the polymerase chain reaction. Nomoto K. Grunewald V. and for which not much therapeutic arms are currently available. References 1. Ramos Nino M.478 Cases without viral infection P valuea 975 comparison of the clinicopathological characteristics between the two groups of breast carcinomas. our study demonstrates for the ﬁrst time the presence of JCV DNA in a subset of breast carcinomas (23% of cases). Murai Y. Stoner GL (1995) BK virus and a new type of JC virus excreted by HIV-1 positive patients in rural Tanzania. the 123 .480 0. JCV DNA was detected in the breast tumor tissues but not in the matched non-tumor breast tissues. In conclusion.743 11 21 24 13 22 21 0.028 13 45 40 9 13 52 41 13 0. doi:10. 3).823 56 2 56 9 0. simian virus 40. Mossman B. Agostini HT. revealed a signiﬁcant correlation between the viral infection and the ‘‘triple negative’’ phenotype of tumors (ER-. Kremmer E. Levin A. Cancer Res 65: 10120–10121. could be an interesting targets for new therapies. ` re de Acknowledgments This study was supported by the ‘‘Ministe ´ rieur.pai. or their antigens. Shao J. Rdzanek MA. Rudzinski JJ. Arthur RR. J Clin Microbiol 34:159–164 4. MMTV-like) in the same tumor P-values were calculated by Fisher’s exact tests (two-sided) and were considered to be statistically signiﬁcant for P \ 0. J Neurovirol 7:345–349 6. Contesso G. doi:10. Tsuneyama K. Arch Virol 140:1919–1934 3. Appl Immunohistochem Mol Morphol 15:394–400. Guinebretiere JM. Carbone M. HER2-). PR-. Hong M. This observation suggests that ‘‘triple negative’’ breast carcinomas are. Stoner GL (1996) Genotype proﬁle of human polyomavirus JC excreted in urine of immunocompetent individuals. Bonnet M.Breast Cancer Res Treat (2012) 133:969–977 Table 2 Comparison of the clinicopathological characteristics between breast carcinomas with and without multiple viral infection Cases with viral infection Age (years) \35 35–50 [50 Histological type Invasive ductal carcinoma Other types Histological gradeb Grade I Grade II Grade III Tumor size (mm) B 20 [ 20 Lymph node metastasesc Negative Positive p53d Negative Positive Estrogen receptord Negative Positive Progesterone receptord Negative Positive HER2d Negative Positive Triple negativee No Yes 48 10 35 23 43 22 56 9 0. Joab I (1999) Detection of Epstein-Barr virus in invasive breast cancers. Abdel-Aziz HO. Further studies are needed to elucidate the role of JCV infection in the breast cancer development or progression.
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