Skip to main content

Advertisement

SpringerLink
Log in

Inflammatory and Non-inflammatory Breast Cancer: A Potential Role for Detection of Multiple Viral DNAs in Disease Progression

  • Breast Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Inflammatory breast cancer (IBC) is the most lethal form of breast cancer. Multiple viral infections in IBC tissues were found to be associated with disease pathogenesis.

Objective

The aim of the present study was to correlate the incidence of viral DNA with breast cancer progression.

Materials and Methods

Overall, 135 women diagnosed with breast cancer were enrolled in this study. Using polymerase chain reaction and sequencing assays, we determined the incidence of human papillomavirus types 16 and 18 (HPV-16 and -18), human cytomegalovirus (HCMV), Epstein–Barr virus, human herpes simplex virus type 1 and 2, and human herpes virus type 8 (HHV-8) in breast carcinoma tissue biopsies. We also assessed the expression of the cell proliferation marker Ki-67 by immunohistochemistry in association with the incidence of viral DNA.

Results

HCMV and HPV-16 were the most detected viral DNAs in breast carcinoma tissues; however, the frequency of HCMV and HHV-8 DNA were significantly higher in IBC than non-IBC tissues. Moreover, the prevalence of multiple viral DNAs was higher in IBC than non-IBC tissues. The incidence of multiple viral DNAs positively correlates with tumor size and number of metastatic lymph nodes in both non-IBC and IBC patients. The expression of Ki-67 was found to be significantly higher in both non-IBC and IBC tissues in which multiple viral DNAs were detected.

Conclusions

The incidence of multiple viral DNAs in IBC tissues was higher compared with non-IBC tissues. The present results suggest the possibility of a functional relationship between the presence of multiple viral DNAs and disease pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Key TJ, Verkasalo PK, Banks E. Epidemiology of breast cancer. Lancet Oncol. 2001;2(3):133–140.

    Article  PubMed  CAS  Google Scholar 

  2. van Diest PJ, van der Wall E, Baak JP. Prognostic value of proliferation in invasive breast cancer: a review. J Clin Pathol. 2004;57(7):675–681.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ellis LM, Fidler IJ. Angiogenesis and metastasis. Eur J Cancer. 1996;32A(14):2451–2460.

    Article  PubMed  CAS  Google Scholar 

  4. Dowsett M, Nielsen TO, A’Hern R, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer Working Group. J Natl Cancer Inst. 2011;103(22):1656–1664.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Schonk DM, Kuijpers HJ, van Drunen E, et al. Assignment of the gene(s) involved in the expression of the proliferation-related Ki-67 antigen to human chromosome 10. Hum Genet. 1989;83(3):297–299.

    Article  PubMed  CAS  Google Scholar 

  6. Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182(3):311–322.

    Article  PubMed  CAS  Google Scholar 

  7. Thor AD, Liu S, Moore DH 2nd, Edgerton SM. Comparison of mitotic index, in vitro bromodeoxyuridine labeling, and MIB-1 assays to quantitate proliferation in breast cancer. J Clin Oncol. 1999;17(2):470–477.

    PubMed  CAS  Google Scholar 

  8. Haroon S, Hashmi AA, Khurshid A, et al. Ki67 index in breast cancer: correlation with other prognostic markers and potential in Pakistani patients. Asian Pac J Cancer Prev. 2013;14(7):4353–4358.

    Article  PubMed  Google Scholar 

  9. Colozza M, Azambuja E, Cardoso F, Sotiriou C, Larsimont D, Piccart MJ. Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now? Ann Oncol. 2005;16(11):1723–1739.

    Article  PubMed  CAS  Google Scholar 

  10. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Taher C, de Boniface J, Mohammad AA, et al. High prevalence of human cytomegalovirus proteins and nucleic acids in primary breast cancer and metastatic sentinel lymph nodes. PloS One. 2013;8(2):e56795.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Tsai JH, Tsai CH, Cheng MH, Lin SJ, Xu FL, Yang CC. Association of viral factors with non-familial breast cancer in Taiwan by comparison with non-cancerous, fibroadenoma, and thyroid tumor tissues. J Med Virol. 2005;75(2):276–281.

    Article  PubMed  Google Scholar 

  13. Wang T, Chang P, Wang L, et al. The role of human papillomavirus infection in breast cancer. Med Oncol. 2012;29(1):48–55.

    Article  PubMed  Google Scholar 

  14. Wang-Johanning F, Frost AR, Johanning GL, et al. Expression of human endogenous retrovirus k envelope transcripts in human breast cancer. Clin Cancer Res. 2001;7(6):1553–1560.

    PubMed  CAS  Google Scholar 

  15. Antonsson A, Bialasiewicz S, Rockett RJ, Jacob K, Bennett IC, Sloots TP. Exploring the prevalence of ten polyomaviruses and two herpes viruses in breast cancer. PloS One. 2012;7(8):e39842.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Cai Q, Chen K, Young KH. Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorders. Exp Mol Med. 2015;47:e133.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Arbach H, Viglasky V, Lefeu F, 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(2):845–853.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Samols MA, Skalsky RL, Maldonado AM, et al. Identification of cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog. 2007;3(5):e65.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Taraboletti G, Benelli R, Borsotti P, et al. Thrombospondin-1 inhibits Kaposi’s sarcoma (KS) cell and HIV-1 Tat-induced angiogenesis and is poorly expressed in KS lesions. J Pathol. 1999;188(1):76–81.

    Article  PubMed  CAS  Google Scholar 

  20. Alibek K, Kakpenova A, Mussabekova A, Sypabekova M, Karatayeva N. Role of viruses in the development of breast cancer. Infect Agent Cancer. 2013;8:32.

    Article  PubMed  PubMed Central  Google Scholar 

  21. El-Shinawi M, Mohamed HT, El-Ghonaimy EA, et al. Human cytomegalovirus infection enhances NF-kappaB/p65 signaling in inflammatory breast cancer patients. PloS One. 2013;8(2):e55755.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Maussang D, Verzijl D, van Walsum M, et al. Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc Natl Acad Sci USA. 2006;103(35):13068–13073.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Skaletskaya A, Bartle LM, Chittenden T, McCormick AL, Mocarski ES, Goldmacher VS. A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation. Proc Natl Acad Sci USA. 2001;98(14):7829–7834.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Munger J, Roizman B. The US3 protein kinase of herpes simplex virus 1 mediates the posttranslational modification of BAD and prevents BAD-induced programmed cell death in the absence of other viral proteins. Proc Natl Acad Sci USA. 2001;98(18):10410–10415.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Ogg PD, McDonell PJ, Ryckman BJ, Knudson CM, Roller RJ. The HSV-1 Us3 protein kinase is sufficient to block apoptosis induced by overexpression of a variety of Bcl-2 family members. Virology. 2004;319(2):212–224.

    Article  PubMed  CAS  Google Scholar 

  26. Simoes PW, Medeiros LR, Simoes Pires PD, et al. Prevalence of human papillomavirus in breast cancer: a systematic review. Int J Gynecol Cancer. 2012;22(3):343–347.

    Article  PubMed  Google Scholar 

  27. Sengupta S, Biarnes MC, Jordan VC. Cyclin dependent kinase-9 mediated transcriptional de-regulation of cMYC as a critical determinant of endocrine-therapy resistance in breast cancers. Breast Cancer Res Treat. 2014;143(1):113–124.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Ferber MJ, Thorland EC, Brink AA, et al. Preferential integration of human papillomavirus type 18 near the c-Myc locus in cervical carcinoma. Oncogene. 2003;22(46):7233–7242.

    Article  PubMed  CAS  Google Scholar 

  29. McMurray HR, McCance DJ. Human papillomavirus type 16 E6 activates TERT gene transcription through induction of c-Myc and release of USF-mediated repression. J Virol. 2003;77(18):9852–9861.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Nouh MA, Mohamed MM, El-Shinawi M, et al. Cathepsin B: a potential prognostic marker for inflammatory breast cancer. J Transl Med. 2011;9:1.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Chang S, Parker SL, Pham T, Buzdar AU, Hursting SD. Inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program of the National Cancer Institute, 1975-1992. Cancer. 1998;82(12):2366–2372.

    Article  PubMed  CAS  Google Scholar 

  32. Damin AP, Karam R, Zettler CG, Caleffi M, Alexandre CO. Evidence for an association of human papillomavirus and breast carcinomas. Breast Cancer Res Treat. 2004;84(2):131–137.

    Article  PubMed  CAS  Google Scholar 

  33. Hennig EM, Suo Z, Thoresen S, Holm R, Kvinnsland S, Nesland JM. Human papillomavirus 16 in breast cancer of women treated for high grade cervical intraepithelial neoplasia (CIN III). Breast Cancer Res Treat. 1999;53(2):121–135.

    Article  PubMed  CAS  Google Scholar 

  34. Guo M, Sneige N, Silva EG, et al. Distribution and viral load of eight oncogenic types of human papillomavirus (HPV) and HPV 16 integration status in cervical intraepithelial neoplasia and carcinoma. Mod Pathol. 2007;20(2):256–266.

    Article  PubMed  CAS  Google Scholar 

  35. Mohamed MM, Sabet S, Peng DF, Nouh MA, El-Shinawi M, El-Rifai W. Promoter hypermethylation and suppression of glutathione peroxidase 3 are associated with inflammatory breast carcinogenesis. Oxid Med Cell Longev. 2014;2014:787195.

    PubMed  PubMed Central  Google Scholar 

  36. El-Ghonaimy EA, El-Shinawi M, Ibrahim SA, et al. Positive lymph-node breast cancer patients: activation of NF-kappaB in tumor-associated leukocytes stimulates cytokine secretion that promotes metastasis via C-C chemokine receptor CCR7. FEBS J. 2015;282(2):271–282.

    Article  PubMed  CAS  Google Scholar 

  37. Mohamed MM, El-Ghonaimy EA, Nouh MA, Schneider RJ, Sloane BF, El-Shinawi M. Cytokines secreted by macrophages isolated from tumor microenvironment of inflammatory breast cancer patients possess chemotactic properties. Int J Biochem Cell Biol. 2014;46:138–147.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Mohamed HT, El-Shinawi M, Nouh MA, et al. Inflammatory breast cancer: high incidence of detection of mixed human cytomegalovirus genotypes associated with disease pathogenesis. Front Oncol. 2014;4:246.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Harkins LE, Matlaf LA, Soroceanu L, et al. Detection of human cytomegalovirus in normal and neoplastic breast epithelium. Herpesviridae. 2010;1(1):8.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Huo Q, Zhang N, Yang Q. Epstein-Barr virus infection and sporadic breast cancer risk: a meta-analysis. PloS One. 2012;7(2):e31656.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Kan CY, Iacopetta BJ, Lawson JS, Whitaker NJ. Identification of human papillomavirus DNA gene sequences in human breast cancer. Br J Cancer. 2005;93(8):946–948.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Lawson JS, Glenn WK, Heng B, et al. Koilocytes indicate a role for human papilloma virus in breast cancer. Br J Cancer. 2009;101(8):1351–1356.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Tsai JH, Hsu CS, Tsai CH, et al. Relationship between viral factors, axillary lymph node status and survival in breast cancer. J Cancer Res Clin Oncol. 2007;133(1):13–21.

    Article  PubMed  Google Scholar 

  44. Gumus M, Yumuk PF, Salepci T, et al. HPV DNA frequency and subset analysis in human breast cancer patients’ normal and tumoral tissue samples. J Exp Clin Cancer Res. 2006;25(4):515–521.

    PubMed  CAS  Google Scholar 

  45. Corbex M, Bouzbid S, Traverse-Glehen A, et al. Prevalence of papillomaviruses, polyomaviruses, and herpesviruses in triple-negative and inflammatory breast tumors from algeria compared with other types of breast cancer tumors. PloS One. 2014;9(12):e114559.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Fimereli D, Gacquer D, Fumagalli D, et al. No significant viral transcription detected in whole breast cancer transcriptomes. BMC Cancer. 2015;15:147.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Tang KW, Alaei-Mahabadi B, Samuelsson T, Lindh M, Larsson E. The landscape of viral expression and host gene fusion and adaptation in human cancer. Nat Commun. 2013;4:2513.

    PubMed  PubMed Central  Google Scholar 

  48. Khabaz MN. Association of Epstein-Barr virus infection and breast carcinoma. Arch Med Sci. 2013;9(4):745–751.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Glenn WK, Heng B, Delprado W, Iacopetta B, Whitaker NJ, Lawson JS. Epstein-Barr virus, human papillomavirus and mouse mammary tumour virus as multiple viruses in breast cancer. PloS One. 2012;7(11):e48788.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Chen T-M, Chang C-F, Chen Y-H, Chen C-A, Wu C-C, Hsieh C-Y. Coexistence of human cytomegalovirus and human papillomavirus type 16 correlates with lymph node metastasis in cervical cancer. J Cancer Res Clin Oncol. 1996;122(10):3.

    Article  Google Scholar 

  51. Mohamed MM, Al-Raawi D, Sabet SF, El-Shinawi M. Inflammatory breast cancer: New factors contribute to disease etiology: a review. J Adv Res. 2014;5(5):525–536.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Al-Raawi D, Abu-El-Zahab H, El-Shinawi M, Mohamed MM. Membrane type-1 matrix metalloproteinase (MT1-MMP) correlates with the expression and activation of matrix metalloproteinase-2 (MMP-2) in inflammatory breast cancer. Int J Clin Exp Med. 2011;4(4):265–275.

    PubMed  CAS  PubMed Central  Google Scholar 

  53. de Oliveira DE, Bacchi MM, Macarenco RS, Tagliarini JV, Cordeiro RC, Bacchi CE. Human papillomavirus and Epstein-Barr virus infection, p53 expression, and cellular proliferation in laryngeal carcinoma. Am J Clin Pathol. 2006;126(2):284–293.

    Article  PubMed  Google Scholar 

  54. Qi ZL, Huo X, Xu XJ, et al. Relationship between HPV16/18 E6 and 53, 21WAF1, MDM2, Ki67 and cyclin D1 expression in esophageal squamous cell carcinoma: comparative study by using tissue microarray technology. Exp Oncol. 2006;28(3):235–240.

    PubMed  CAS  Google Scholar 

  55. Mate JL, Ariza A, Munoz A, Molinero JL, Lopez D, Navas-Palacios JJ. Induction of proliferating cell nuclear antigen and Ki-67 expression by cytomegalovirus infection. J Pathol. 1998;184(3):279–282.

    Article  PubMed  CAS  Google Scholar 

  56. Zheng X, Hu L, Chen F, Christensson B. Expression of Ki67 antigen, epidermal growth factor receptor and Epstein-Barr virus-encoded latent membrane protein (LMP1) in nasopharyngeal carcinoma. Eur J Cancer B. 1994;30B(5):290–295.

    Article  CAS  Google Scholar 

Download references

Acknowledgment

This work was conducted at the Cancer Biology Research Laboratory (CBRL), Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt, and was supported by Avon Foundation Grants # 02-2009-085 a and b (Robert J. Schneider and Mona Mostafa Mohamed). A special thanks to Dr. Yasser Hassane, Summit Urgent Care, Macomb, MI, USA, for donating the reagents used in this study.

Disclosure

Mohamed El-Shinawi, Hossam Taha Mohamed, Hadeer Hesham Abdel-Fattah, Sherif Abdel Aziz Ibrahim, Medhat S. El-Halawany, M. Akram Nouh, Robert J. Schneider, and Mona Mostafa Mohamed declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author information

Author notes

    Authors and Affiliations

    1. Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt

      Mohamed El-Shinawi MD

    2. Cancer Biology Research Lab, Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt

      Hossam Taha Mohamed PhD, Hadeer Hesham Abdel-Fattah BSc, Sherif Abdel Aziz Ibrahim PhD, Medhat S. El-Halawany PhD & Mona Mostafa Mohamed PhD

    3. Department of Pathology, National Cancer Institute, Cairo University, Giza, Egypt

      M. Akram Nouh MD

    4. Department of Microbiology, School of Medicine, New York University, New York, NY, USA

      Robert J. Schneider PhD

    Authors
    1. Mohamed El-Shinawi MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Hossam Taha Mohamed PhD
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Hadeer Hesham Abdel-Fattah BSc
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Sherif Abdel Aziz Ibrahim PhD
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Medhat S. El-Halawany PhD
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. M. Akram Nouh MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Robert J. Schneider PhD
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Mona Mostafa Mohamed PhD
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Hossam Taha Mohamed PhD.

    Additional information

    Mohamed El-Shinawi and Hossam Taha Mohamed have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 33 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    El-Shinawi, M., Mohamed, H.T., Abdel-Fattah, H.H. et al. Inflammatory and Non-inflammatory Breast Cancer: A Potential Role for Detection of Multiple Viral DNAs in Disease Progression. Ann Surg Oncol 23, 494–502 (2016). https://doi.org/10.1245/s10434-015-4888-2

    Download citation

    • Received:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1245/s10434-015-4888-2

    Keywords

    Search

    Navigation