Skip to main content

Advertisement

SpringerLink
Log in

Circulating levels and clinical implications of epithelial membrane antigen and cytokeratin-1 in women with breast cancer: can their ratio improve the results?

  • Research Article
  • Published:
Tumor Biology

Abstract

Immunohistochemical studies proved that the presence of breast cancer (BrCa) is accompanied by elevated levels of epithelial membrane antigen (EMA) and decreased levels of cytokeratin-1 (CK1). We, therefore, hypothesize that the serum EMA/CK1 ratio may serve as a promising biomarker for early diagnosis of breast cancer. The circulating levels of EMA and CK1 were determined by Western blot and enzyme-linked immunosorbent assay (ELISA) in sera from 102 women with BrCa and 90 women as controls (40 with benign breast disease and 50 healthy). EMA at 130 kDa and CK1 at 67 kDa were identified, purified, and quantified in sera of BrCa patients using ELISA. EMA/CK1 ratio values were found to discriminate BrCa patients from controls (P < 0.0001) with high diagnostic ability (area under the curve [AUC] = 0.901, sensitivity = 82, specificity = 76). The sensitivity and specificity for early-stage (≤T2) BrCa were 72 and 76 %, respectively. The ratio values of patients with late-stage (>T2) tumors were significantly higher than those of patients with early-stage (≤T2) tumors. Moreover, higher grades (grades 2–3) were associated with higher values than grade 1 tumors. AUC values in different BrCa patients who had early stage, low grade, or size ≤2 cm were 0.855, 0.762, and 0.839, respectively. AUC values of patients with positive lymph node or positive distant metastasis were 0.907 and 0.913, respectively. We show for the first time the impact of serum EMA and CK1 ratio in BrCa detection. Differential EMA/CK1 values may serve as a diagnostic marker in early-stage breast cancer patients.

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. Travier N, Fonseca-Nunes A, Javierre C, et al. Effect of a diet and physical activity intervention on body weight and nutritional patterns in overweight and obese breast cancer survivors. Med Oncol. 2014;31:783.

    Article  CAS  PubMed  Google Scholar 

  2. Wang PY, Gong HT, Li BF, et al. Higher expression of circulating miR-182 as a novel biomarker for breast cancer. Oncol Lett. 2013;6:1681–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Corsetti V, Houssami N, Ghirardi M, et al. Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. Eur J Cancer. 2011;47:1021–6.

    Article  PubMed  Google Scholar 

  4. Tabár L, Vitak B, Chen TH-H, et al. Swedish two-county trial: impact of mammographic screening on breast cancer mortality during 3 decades. Radiology. 2011;260:658–63.

    Article  PubMed  Google Scholar 

  5. Zhang G, Sun X, Lv H, Yang X, Kang X. Serum amyloid A: a new potential serum marker correlated with the stage of breast cancer. Oncol Lett. 2012;3:940–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287–312.

    Article  CAS  PubMed  Google Scholar 

  7. Sun Y, Zhang R, Wang M, Zhang Y, Qi J, Li J. SOX2 autoantibodies as noninvasive serum biomarker for breast carcinoma. Cancer Epidemiol Biomarkers Prev. 2012;21:2043–7.

    Article  CAS  PubMed  Google Scholar 

  8. Nath S, Mukherjee P. MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med. 2014;20:332–42.

    Article  CAS  PubMed  Google Scholar 

  9. Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol. 2008;70:431–57.

    Article  CAS  PubMed  Google Scholar 

  10. Kufe DW. MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene. 2013;32:1073–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Taylor-Papadimitriou J. Report on the first international workshop on carcinoma-associated mucins. Int J Cancer. 1991;49:1–5.

    Article  CAS  PubMed  Google Scholar 

  12. Gion M, Mione R, Leon AE, Dittadi R. Comparison of the diagnostic accuracy of CA27.29 and CA15.3 in primary breast cancer. Clin Chem. 1999;45:630–7.

    CAS  PubMed  Google Scholar 

  13. Attallah AM, Abdallah SO, El Sayed AS, et al. Non-invasive predictive score of fibrosis stages in chronic hepatitis C patients based on epithelial membrane antigen in the blood in combination with routine laboratory markers. Hepatol Res. 2011;41:1075–84.

    Article  CAS  PubMed  Google Scholar 

  14. Smolarz B, Krawczyk T, Westfal B, et al. Comparison of one-step nucleic acid amplification (OSNA) method and routine histological investigation for intraoperative detection of lymph node metastasis in Polish women with breast cancer. Pol J Pathol. 2013;64:104–8.

    Article  CAS  PubMed  Google Scholar 

  15. Oloomi M, Yardehnavi N, Bouzari S, Moazzezy N. Non-coding CK19 RNA in peripheral blood and tissue of breast cancer patients. Acta Med Iran. 2013;51:75–86.

    CAS  PubMed  Google Scholar 

  16. Alshareeda AT, Soria D, Garibaldi JM, et al. Characteristics of basal cytokeratin expression in breast cancer. Breast Cancer Res Treat. 2013;139:23–37.

    Article  CAS  PubMed  Google Scholar 

  17. Shao MM, Chan SK, Yu AM, et al. Keratin expression in breast cancers. Virchows Arch. 2012;461:313–22.

    Article  CAS  PubMed  Google Scholar 

  18. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970;227:680–5.

    Article  CAS  PubMed  Google Scholar 

  19. Towbin H, Stachlin T, Gordou J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets procedure and some applications. Proc Natl Acad Sci U S A. 1979;76:4350–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Attallah AM, Helmi H, el-Helali E, el-Mohamadi H. A dipstick, dot-ELISA assay for the rapid and early detection of bladder cancer. Cancer Detect Prev. 1991;15:495–9.

    CAS  PubMed  Google Scholar 

  21. Attallah AM, El-Far M, Abdel Malak CA, et al. Evaluation of cytokeratin-1 in the diagnosis of hepatocellular carcinoma. Clin Chim Acta. 2011;412:2310–5.

    Article  CAS  PubMed  Google Scholar 

  22. Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem. 1993;39:561–77.

    CAS  PubMed  Google Scholar 

  23. Cheever MA, Allison JP, Ferris AS, et al. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009;15:5323–37.

    Article  PubMed  Google Scholar 

  24. Sinn BV, von Minckwitz G, Denkert C, et al. Evaluation of Mucin-1 protein and mRNA expression as prognostic and predictive markers after neoadjuvant chemotherapy for breast cancer. Ann Oncol. 2013;24:2316–24.

    Article  CAS  PubMed  Google Scholar 

  25. Croce MV, Isla-Larrain MT, Demichelis SO, Gori JR, Price MR, Segal-Eiras A. Tissue and serum MUC1 mucin detection in breast cancer patients. Breast Cancer Res Treat. 2003;81:195–207.

    Article  CAS  PubMed  Google Scholar 

  26. Schroeder JA, Masri AA, Adriance MC, et al. MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation. Oncogene. 2004;23:5739–47.

    Article  CAS  PubMed  Google Scholar 

  27. Croce MV, Isla-Larrain MT, Rua CE, Rabassa ME, Gendler SJ, Segal-Eiras A. Patterns of MUC1 tissue expression defined by an anti-MUC1 cytoplasmic tail monoclonal antibody in breast cancer. J Histochem Cytochem. 2003;51:781–8.

    Article  CAS  PubMed  Google Scholar 

  28. Bratthauer GL, Moinfar F, Stamatakos MD, et al. Combined E-cadherin and high molecular weight cytokeratin immunoprofile differentiates lobular, ductal, and hybrid mammary intraepithelial neoplasias. Hum Pathol. 2002;33:620–7.

    Article  CAS  PubMed  Google Scholar 

  29. Boecker W, Buerger H, Schmitz K, et al. Ductal epithelial proliferations of the breast: a biological continuum? Comparative genomic hybridization and high-molecular-weight cytokeratin expression patterns. J Pathol. 2001;195:415–21.

    Article  CAS  PubMed  Google Scholar 

  30. Rakha EA, Boyce RW, Abd El-Rehim D, et al. Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer. Mod Pathol. 2005;18:1295–304.

    Article  CAS  PubMed  Google Scholar 

  31. Spicer AP, Rowse GJ, Lidner TK, Gendler SJ. Delayed mammary tumor progression in Muc-1 null mice. J Biol Chem. 1995;270:30093–101.

    Article  CAS  PubMed  Google Scholar 

  32. Schroeder JA, Adriance MC, Thompson MC, Camenisch TD, Gendler SJ. MUC1 alters betacatenin-dependent tumor formation and promotes cellular invasion. Oncogene. 2003;22:1324–32.

    Article  CAS  PubMed  Google Scholar 

  33. Merlo G, Siddiqui J, Cropp C, et al. DF3 tumor-associated antigen gene is located in a region on chromosome 1q frequently altered in primary human breast cancer. Cancer Res. 1989;49:6966–71.

    CAS  PubMed  Google Scholar 

  34. Lacunza E, Baudis M, Colussi AG, Segal-Eiras A, Croce MV, Abba MC. MUC1 oncogene amplification correlates with protein overexpression in invasive breast carcinoma cells. Cancer Genet Cytogenet. 2010;201:102–10.

    Article  CAS  PubMed  Google Scholar 

  35. Khodarev N, Ahmad R, Rajabi H, et al. Cooperativity of the MUC1 oncoprotein and STAT1 pathway in poor prognosis human breast cancer. Oncogene. 2010;29:920–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Ahmad R, Raina D, Joshi MD, Kawano T, Kharbanda S, Kufe D. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69:7013–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Abe M, Kufe D. Transcriptional regulation of the DF3 gene expression in human MCF-7 breast carcinoma cells. J Cell Physiol. 1990;143:226–31.

    Article  CAS  PubMed  Google Scholar 

  38. Abe M, Kufe D. Characterization of cis-acting elements regulating transcription of the human DF3 breast carcinoma-associated antigen (MUC1) gene. Proc Natl Acad Sci U S A. 1993;90:282–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Rajabi H, Jin C, Ahmad R, McClary C, Kufe D. Mucin 1 oncoprotein expression is suppressed by the miR-125b oncomir. Genes Cancer. 2010;1:62–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Sachdeva M, Mo YY. MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. Cancer Res. 2010;70:378–87.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Whittock NV, Ashton GH, Griffiths WA, Eady RA, McGrath JA. New mutations in keratin 1 that cause bullous congenital ichthyosiform erythroderma and keratin 2e that cause ichthyosis bullosa of Siemens. Br J Dermatol. 2001;145:330–5.

    Article  CAS  PubMed  Google Scholar 

  42. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science. 1994;265:2088–90.

    Article  CAS  PubMed  Google Scholar 

  43. Tirkkonen M, Johannsson O, Agnarsson BA, et al. Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res. 1997;57:1222–7.

    CAS  PubMed  Google Scholar 

  44. Knuutila S, Aalto Y, Autio K, et al. DNA copy number losses in human neoplasms. Am J Pathol. 1999;155:683–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Hewala TI, Abd El-Monaim NA, Anwar M, Ebied SA. The clinical significance of serum soluble Fas and p53 protein in breast cancer patients: comparison with serum CA 15-3. Pathol Oncol Res. 2012;18:841–8.

    Article  CAS  PubMed  Google Scholar 

  46. Guadagni F, Ferroni P, Carlini S, et al. A re-evaluation of carcinoembryonic antigen (CEA) as a serum marker for breast cancer: a prospective longitudinal study. Clin Cancer Res. 2001;7:2357–62.

    CAS  PubMed  Google Scholar 

  47. Marić P, Ozretić P, Levanat S, Oresković S, Antunac K, Beketić-Oresković L. Tumor markers in breast cancer—evaluation of their clinical usefulness. Coll Antropol. 2011;35:241–7.

    PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the staff of the Mansoura University Oncology Center, Mansoura, Egypt, for their assistances in this study. This work has been completely supported financially and carried out at the Biotechnology Research Center, New Damietta, Egypt.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Research & Development Department, Biotechnology Research Center, P.O. Box (14), 23 July St., Industrial Zone, New Damietta, 34517, Egypt

    Abdelfattah M. Attallah, Mohamed A. Abdelrazek, Ahmed A. Attallah, Mohamed A. Elweresh, Gamal E. Abdel Hameed, Hadil A. Shawki & Karim S. Salama

  2. Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt

    Mohamed El-Far & Ahmed M. El-Waseef

  3. Chemistry Department, Faculty of Science, Helwan University, Cairo, Egypt

    Mohamed M. Omran

  4. Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt

    Sanaa O. Abdallah & Mohamed A. El-desouky

  5. Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt

    Ibrahim El-Dosoky

Authors
  1. Abdelfattah M. Attallah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohamed El-Far
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohamed M. Omran
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sanaa O. Abdallah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohamed A. El-desouky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ibrahim El-Dosoky
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohamed A. Abdelrazek
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ahmed A. Attallah
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mohamed A. Elweresh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gamal E. Abdel Hameed
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hadil A. Shawki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Karim S. Salama
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ahmed M. El-Waseef
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abdelfattah M. Attallah.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Attallah, A.M., El-Far, M., Omran, M.M. et al. Circulating levels and clinical implications of epithelial membrane antigen and cytokeratin-1 in women with breast cancer: can their ratio improve the results?. Tumor Biol. 35, 10737–10745 (2014). https://doi.org/10.1007/s13277-014-2375-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2375-1

Keywords

Search

Navigation