Skip to main content

HCV nonstructural protein 4 is associated with aggressiveness features of breast cancer



Hepatitis C virus (HCV) has the lymphotropic feature that is supposed to be the reason of related extrahepatic manifestation. HCV viral oncoproteins may participate in the regulation of some gene expression that has been implicated in tumorigenesis. Our aim is to evaluate the HCV-NS4 circulating levels in breast cancer (BC) and to investigate its relation with BC tumor aggressiveness.


This study was performed among 158 Egyptian women (120 with BC and 38 with benign breast diseases). ELISA was used for detection of anti-HCV antibodies, HCV-NS4, fibronectin, and CA 15-3.


No association between HCV detection in this group of BC patients (27.5% in BC vs. 23.7% in breast benign diseases, P = 0.687). Among HCV-infected patients, the mean HCV-NS4 serum level in BC was significantly higher than benign group (61.7 μg/mL vs. 33.9 μg/mL, P = 0.0005). Fibronectin levels were higher (P = 0.014) in patients infected with HCV than noninfected BC patients. Elevated HCV-NS4 levels were associated with tumor severity features like large size, late stages, high grades, and infiltrated lymph nodes. The elevated levels of HCV-NS4 (> 40 μg/mL) yielded an estimated odds ratio (95% confidence intervals) of 2.5 (0.98–6.36), 1.2 (0.44–3.33), 1.9 (0.53–7.00), and 2.5 (0.87–7.33) for developing large size, late stages, high grades, and infiltrated lymph nodes, respectively. Interestingly, HCV-NS4 levels significantly correlated with other BC tumor marker like CA15-3 (r = 0.535; P = 0.0009) and fibronectin (r = 0.432; P < 0.0001).


HCV-NS4 appears to be associated with BC progression features. Oncologists treating such BC patients should consider HCV screening to enable the early identification and to prevent progression of the disease.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  1. 1.

    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. Cancer J Clin. 2015;65:87–108.

    Article  Google Scholar 

  2. 2.

    Hamilton R, Williams JK, Bowers BJ, Calzone K. Life trajectories, genetic testing, and risk reduction decisions in 18–39 year old women at risk for hereditary breast and ovarian cancer. J Genet Couns. 2009;18:147–59.

    Article  PubMed  Google Scholar 

  3. 3.

    Richardson A. Is breast cancer caused by late exposure to a common virus? Med Hypotheses. 1997;48:491–7.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Fiorino S, Bacchi-Reggiani L, De Biase D, et al. Possible association between hepatitis C virus and malignancies different from hepatocellular carcinoma: a systematic review. World J Gastroenterol. 2015;21:12896–953.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Carrozzo M, Quadri R, Latorre P, et al. Molecular evidence that the hepatitis C virus replicates in the oral mucosa. J Hepatol. 2002;37:364–9.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Crovatto M, Pozzato G, Zorat F, et al. Peripheral blood neutrophils from hepatitis C virus-infected patients are replication sites of the virus. Haematologica. 2000;85:356–61.

    CAS  PubMed  Google Scholar 

  7. 7.

    Sansonno D, Lauletta G, Montrone M, Grandaliano G, Schena FP, Dammacco F. Hepatitis C virus RNA and core protein in kidney glomerular and tubular structures isolated with laser capture microdissection. Clin Exp Immunol. 2005;140:498–506.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Toussirot E, Le Huede G, Mougin C, Balblanc JC, Bettinger D, Wendling D. Presence of hepatitis C virus RNA in the salivary glands of patients with Sjogren’s syndrome and hepatitis C virus infection. J Rheumatol. 2002;29:2382–5.

    CAS  PubMed  Google Scholar 

  9. 9.

    Kurokawa M, Hidaka T, Sasaki H, Nishikata I, Morishita K, Setoyama M. Analysis of hepatitis C virus (HCV) RNA in the lesions of lichen planus in patients with chronic hepatitis C: detection of anti-genomic- as well as genomic-strand HCV RNAs in lichen planus lesions. J Dermatol Sci. 2003;32:65–70.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Fm Yan, As Chen, Hao F, et al. Hepatitis C virus may infect extrahepatic tissues in patients with hepatitis C. World J Gastroenterol. 2000;6:805–11.

    Article  Google Scholar 

  11. 11.

    Su Fh, Sn Chang, Pc Chen, Sung Fc Su, Ct Yeh Cc. Association between chronic viral hepatitis infection and breast cancer risk: a nationwide population-based case-control study. Bmc Cancer. 2011;11:495.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Larrey D, Bozonnat MC, Kain I, Pageaux GP, Assenat E. Is chronic hepatitis C virus infection a risk factor for breast cancer? World J Gastroenterol. 2010;16:3687–91.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Mclaughlin-Drubin ME, Munger K. Viruses associated with human cancer. Biochim Biophys Acta. 2008;1782:127–50.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Jj Zhou, Rf Chen, Xg Deng, et al. Hepatitis C virus core protein regulates nanog expression via the stat3 pathway. FEBS Lett. 2014;588:566–73.

    Article  Google Scholar 

  15. 15.

    My Chen, Zq Huang, Lz Chen, Yb Gao, Ry Peng, Dw Wang. Detection of hepatitis C virus Ns5 protein and genome in chinese carcinoma of the extrahepatic bile duct and its significance. World J Gastroenterol. 2000;6:800–4.

    Article  Google Scholar 

  16. 16.

    Takaki A, Tatsukawa M, Iwasaki Y, et al. Hepatitis C virus Ns4 protein impairs the Th1 polarization of immature dendritic cells. J Viral Hepat. 2010;17:555–62.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Attallah AM, Ismail H, Shiha GE, Abou-Dobara MI, El-Sherbiny RE, El-Dosoky I. Immunochemical identification and partial characterization of a native hepatitis C viral non-structural 4 antigen in sera of HCV infected patients. Clin Chim Acta. 2008;388:115–22.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Attallah AM, Zahran F, Ismail H, Omran MM, El-Dosoky I, Shiha GE. Immunochemical identification and detection of serum fibronectin in liver fibrosis patients with chronic hepatitis C. J Immunoassay Immunochem. 2007;28:331–42.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Jm Pawlotsky, Ben Yahia M, Andre C, et al. Immunological disorders in C virus chronic active hepatitis: a prospective case-control study. Hepatology. 1994;19:841–8.

    Article  Google Scholar 

  20. 20.

    Chen Y, Williams V, Filippova M, Filippov V, Duerksen-Hughes P. Viral carcinogenesis: factors inducing DNA damage and virus integration. Cancers (Basel). 2014;6:2155–86.

    CAS  Article  Google Scholar 

  21. 21.

    Ak Witkiewicz, Es Knudsen. Retinoblastoma tumor suppressor pathway in breast cancer: prognosis, precision medicine, and therapeutic interventions. Breast Cancer Res. 2014;16:207.

    Google Scholar 

  22. 22.

    Munakata T, Nakamura M, Liang Y, Li K, Lemon SM. Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus Ns5b RNA-dependent rna polymerase. Proc Natl Acad Sci USA. 2005;102:18159–64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Qadri I, Iwahashi M, Simon F. Hepatitis C virus Ns5a protein binds Tbp and P53, inhibiting their DNA binding and p53 interactions with Tbp and Ercc3. Biochim Biophys Acta. 2002;1592:193–204.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Sakamuro D, Furukawa T, Takegami T. Hepatitis C virus nonstructural protein Ns3 transforms Nih 3t3 cells. J Virol. 1995;69:3893–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Song LL, Miele L. Cancer stem cells–an old idea that’s new again: implications for the diagnosis and treatment of breast cancer. Expert Opin Biol Ther. 2007;7:431–8.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Ali N, Allam H, May R, et al. Hepatitis C virus-induced cancer stem cell-like signatures in cell culture and murine tumor xenografts. J Virol. 2011;85:12292–303.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Fernandez-Garcia B, Eiro N, Marin L, et al. Expression and prognostic significance of fibronectin and matrix metalloproteases in breast cancer metastasis. Histopathology. 2014;64:512–22.

    Article  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Abdelfattah M. Attallah.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Attallah, A.M., El-Far, M., Abdelrazek, M.A. et al. HCV nonstructural protein 4 is associated with aggressiveness features of breast cancer. Breast Cancer 25, 297–302 (2018).

Download citation


  • Breast cancer
  • Hepatitis C virus
  • Viral proteins
  • HCV-NS4
  • Extrahepatic malignancies