Skip to main content

Advertisement

SpringerLink
Log in

Elevated Hu-Antigen Receptor (HuR) Expression is Associated with Tumor Aggressiveness and Poor Prognosis but not with COX-2 Expression in Invasive Breast Carcinoma Patients

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

Hu-antigen R (HuR), a RNA-binding protein, is considered to play a crucial role in tumor development and progression by stabilizing or regulating a group of cellular mRNAs of cancer-related genes, such as cyclooxygenase-2 (COX-2). The present study aimed to evaluate the clinical significance of HuR and COX-2 expression in invasive breast carcinoma. HuR and COX-2 protein expression was assessed immunohistochemically on paraffin-embedded breast cancer tissue sections obtained from 121 patients and was statistically analyzed with clinicopathological parameters, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), as well as with tumor cells’ proliferative capacity and overall and disease-free patients’ survival. High HuR expression was positively associated with larger tumor size and advanced disease stage (p = 0.0234 and p = 0.0361, respectively), being more frequently observed in ER negative cases (p = 0.0208). High COX-2 expression was negatively associated with histological (p < 0.0001) and nuclear (p = 0.0033) grade and tumor cells’ proliferative rate (p = 0.0015), being more frequently observed in luminal-A compared to other molecular subtypes (p = 0.0221). High HuR expression was associated with poor overall and disease-free patients’ survival at both univariate (log-rank test, p = 0.0092 and p = 0.0004, respectively) and multivariate (Cox-regression analysis, p = 0.0223 and p = 0.0004, respectively) level. On the other hand, high COX-2 expression was associated with favorable overall and disease-free patients’ survival merely at univariate level (log-rank test, p = 0.0389 and p = 0.0154, respectively). HuR expression was not associated with COX-2 expression (Spearman R = 0.1489, p = 0.1032). The present data support evidence that HuR is associated with tumor aggressiveness and poor prognosis in breast carcinoma, reinforcing its potential as promising therapeutic target in this type of neoplasia.

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. Ma WJ, Cheng S, Campbell C, Wright A, Furneaux H (1996) Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J Biol Chem 271:8144–81451

    Article  PubMed  CAS  Google Scholar 

  2. Burd CG, Dreyfuss G (1994) Conserved structures and diversity of functions of RNA-binding proteins. Science 265:615–621

    Article  PubMed  CAS  Google Scholar 

  3. Lopez de Silanes I, Zhan M, Lal A, Yang X, Gorospe M (2004) Identification of a target RNA motif for RNA-binding protein HuR. Proc Natl Acad Sci U S A 101:2987–2992

    Article  PubMed  CAS  Google Scholar 

  4. Brennan CM, Steitz JA (2001) HuR and mRNA stability. Cell Mol Life Sci 58:266–277

    Article  PubMed  CAS  Google Scholar 

  5. Kullmann M, Gopfert U, Siewe B, Hengst L (2002) ELAV/Hu proteins inhibit p27 translation via an IRES element in the p27 5'UTR. Genes Dev 16:3087–3099

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Mazan-Mamczarz K, Galban S, Lopez de Silanes I et al (2003) RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiation. Proc Natl Acad Sci U S A 100:8354–8359

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Zhu H, Zhou HL, Hasman RA, Lou H (2007) Hu proteins regulate polyadenylation by blocking sites containing U-rich sequences. J Biol Chem 282:2203–2210

    Article  PubMed  CAS  Google Scholar 

  8. Fan XC, Steitz JA (1998) HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc Natl Acad Sci U S A 95:15293–11528

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Keene JD (1999) Why is Hu where? Shuttling of early-response-gene messenger RNA subsets. Proc Natl Acad Sci U S A 96:5–7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Khan Z, Khan N, Tiwari RP, Sah NK, Prasad GB, Bisen PS (2011) Biology of COX-2: an application in cancer therapeutics. Curr Drug Targets 12:1082–1093

    Article  PubMed  CAS  Google Scholar 

  11. Ghosh N, Chaki R, Mandal V, Mandal SC (2010) COX-2 as a target for cancer chemotherapy. Pharmacol Rep 62:233–244

    Article  PubMed  CAS  Google Scholar 

  12. Skibinski A, Kuperwasser C (2015) The origin of breast tumor heterogeneity. Oncogene 34:5309–5316

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Ulaner GA, Riedl CC, Dickler MN, Jhaveri K, Pandit-Taskar N, Weber W (2016) Molecular imaging of biomarkers in breast cancer. J Nucl Med 57:53S–59S

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Kos Z, Dabbs DJ (2016) Biomarker assessment and molecular testing for prognostication in breast cancer. Histopathology 68:70–85

    Article  PubMed  Google Scholar 

  15. Kotta-Loizou I, Giaginis C, Theocharis S (2014) Clinical significance of HuR expression in human malignancy. Med Oncol 31:161

    Article  PubMed  CAS  Google Scholar 

  16. Rhee WJ, Ni CW, Zheng Z, Chang K, Jo H, Bao G (2010) HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells. Proc Natl Acad Sci U S A 107:6858–6863

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zhang J, Modi Y, Yarovinsky T et al (2012) Macrophage beta2 integrin-mediated, HuR-dependent stabilization of angiogenic factor-encoding mRNAs in inflammatory angiogenesis. Am J Pathol 180:1751–1760

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Lopez de Silanes I, Lal A, Gorospe M (2005) HuR: post-transcriptional paths to malignancy. RNA Biol 2:11–13

    Article  PubMed  CAS  Google Scholar 

  19. Giaginis C, Alexandrou P, Tsoukalas N et al (2015) Hu-antigen receptor (HuR) and cyclooxygenase-2 (COX-2) expression in human non-small cell lung carcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients’ survival. Tumour Biol 36:315–327

    Article  PubMed  CAS  Google Scholar 

  20. Abdelmohsen K, Srikantan S, Kuwano Y, Gorospe M (2008) miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels. Proc Natl Acad Sci U S A 105:20297–20302

    Article  PubMed  PubMed Central  Google Scholar 

  21. Abdelmohsen K, Kim MM, Srikantan S et al (2010) miR-519 suppresses tumor growth by reducing HuR levels. Cell Cycle 9:1354–1359

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Srikantan S, Gorospe M (2012) HuR function in disease. Front Biosci (Landmark Ed) 17:189–205

    Article  CAS  Google Scholar 

  23. Saunus JM, French JD, Edwards SL et al (2008) Posttranscriptional regulation of the breast cancer susceptibility gene BRCA1 by the RNA binding protein HuR. Cancer Res 68:9469–9478

    Article  PubMed  CAS  Google Scholar 

  24. Denkert C, Weichert W, Winzer KJ et al (2004) Expression of the ELAV-like protein HuR is associated with higher tumor grade and increased cyclooxygenase-2 expression in human breast carcinoma. Clin Cancer Res 10:5580–5586

    Article  PubMed  CAS  Google Scholar 

  25. Heinonen M, Hemmes A, Salmenkivi K et al (2011) Role of RNA binding protein HuR in ductal carcinoma in situ of the breast. J Pathol 224:529–539

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Zhu Z, Wang B, Bi J et al (2013) Cytoplasmic HuR expression correlates with P-gp, HER-2 positivity, and poor outcome in breast cancer. Tumour Biol 34:2299–2308

    Article  PubMed  CAS  Google Scholar 

  27. Wang J, Li D, Wang B, Wu Y (2013) Predictive and prognostic significance of cytoplasmic expression of ELAV-like protein HuR in invasive breast cancer treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 141:213–224

    Article  PubMed  CAS  Google Scholar 

  28. Heinonen M, Bono P, Narko K et al (2005) Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma. Cancer Res 65:2157–2161

    Article  PubMed  CAS  Google Scholar 

  29. Heinonen M, Fagerholm R, Aaltonen K et al (2007) Prognostic role of HuR in hereditary breast cancer. Clin Cancer Res 13:6959–6963

    Article  PubMed  CAS  Google Scholar 

  30. Yuan Z, Sanders AJ, Ye L, Wang Y, Jiang WG (2011) Prognostic value of the human antigen R (HuR) in human breast cancer: high level predicts a favourable prognosis. Anticancer Res 31:303–310

    PubMed  CAS  Google Scholar 

  31. Ortega AD, Sala S, Espinosa E, Gonzalez-Baron M, Cuezva JM (2008) HuR and the bioenergetic signature of breast cancer: a low tumor expression of the RNA-binding protein predicts a higher risk of disease recurrence. Carcinogenesis 29:2053–2061

    Article  PubMed  CAS  Google Scholar 

  32. Tavassoli FA, Devilee P (eds) (2003) Pathology and genetics tumors of the breast and female genital organs. IARC WHO classification of tumors, no. 4. WHO Press, Lyon, pp 25–27

    Google Scholar 

  33. Hermanek P, Sabin H (eds) (1992) TNM classification of international union against cancer. In TNM atlas, 3rd rev, 4th edn. Springer-Verlag, Berlin, pp 15–25

    Google Scholar 

  34. Robins P, Pinder S, de Klerk N (1995) Histological grading of breast carcinomas: a study of interobserver agreement. Hum Pathol 6:873–879

    Article  Google Scholar 

  35. Mylona E, Vamvakaris I, Giannopoulou I et al (2013) An immunohistochemical evaluation of the proteins Wnt1 and glycogen synthase kinase (GSK)-3β in invasive breast carcinomas. Histopathology 62:899–907

    Article  PubMed  Google Scholar 

  36. Michailidi C, Giaginis C, Stolakis V et al (2010) Evaluation of FAK and Src expression in human benign and malignant thyroid lesions. Pathol Oncol Res 16:497–507

    Article  PubMed  CAS  Google Scholar 

  37. Giaginis C, Alexandrou P, Delladetsima I, Giannopoulou I, Patsouris E, Theocharis S (2014) Clinical significance of histone deacetylase (HDAC)-1, HDAC-2, HDAC-4, and HDAC-6 expression in human malignant and benign thyroid lesions. Tumour Biol 35:61–71

    Article  PubMed  CAS  Google Scholar 

  38. Mylona E, Melissaris S, Nomikos A et al (2014) Effect of BRCA1 immunohistochemical localizations on prognosis of patients with sporadic breast carcinomas. Pathol Res Pract 210:533–540

    Article  PubMed  CAS  Google Scholar 

  39. Giaginis C, Alexandrou P, Delladetsima I et al (2016) Clinical significance of Hu-antigen receptor (HuR) and cyclooxygenase-2 (COX-2) expression in human malignant and benign thyroid lesions. Pathol Oncol Res 22:189–196

    Article  PubMed  CAS  Google Scholar 

  40. Hammond MEH, Hayes DF, Dowsett M et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2786–2795

    Article  Google Scholar 

  41. Wolff AC, Hammond ME, Hicks DG et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997–3401

    Article  PubMed  Google Scholar 

  42. Nakopoulou L, Mylona E, Papadaki I et al (2005) Overexpression of cyclooxygenase-2 is associated with a favorable prognostic phenotype in breast carcinoma. Pathobiology 72:241–249

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. First Department of Pathology, Medical School, University of Athens, Athens, Greece

    Constantinos Giaginis, Anastasia Sampani, Iolly Kotta-Loizou, Ioanna Giannopoulou, Eugene Danas, Ekaterini Politi, Efstratios Patsouris, Lydia Nakopoulou & Stamatios Theocharis

  2. Department of Food Science and Nutrition, University of the Aegean, Myrina, Lemnos, Greece

    Constantinos Giaginis

  3. Second Department of Propedeutic Surgery, Medical School, University of Athens, Athens, Greece

    Gerasimos Tsourouflis & Gregorios Kouraklis

  4. Department of Clinical Therapeutics, Alexandra General Hospital, Medical School, University of Athens, Athens, Greece

    Antonios Keramopoulos

  5. First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias str., Goudi, GR11527, Athens, Greece

    Stamatios Theocharis

Authors
  1. Constantinos Giaginis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anastasia Sampani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Iolly Kotta-Loizou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ioanna Giannopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eugene Danas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ekaterini Politi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gerasimos Tsourouflis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gregorios Kouraklis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Efstratios Patsouris
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Antonios Keramopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lydia Nakopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Stamatios Theocharis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stamatios Theocharis.

Ethics declarations

Conflict of Interest

All authors verify that they have not accepted any funding or support from an organization that may in any way gain or lose financially from the results of the present study. All authors verify that they have not been employed by an organization that may in any way gain or lose financially from the results of the present study. None authors have any other conflicting interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Giaginis, C., Sampani, A., Kotta-Loizou, I. et al. Elevated Hu-Antigen Receptor (HuR) Expression is Associated with Tumor Aggressiveness and Poor Prognosis but not with COX-2 Expression in Invasive Breast Carcinoma Patients. Pathol. Oncol. Res. 24, 631–640 (2018). https://doi.org/10.1007/s12253-017-0288-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-017-0288-1

Keywords

Search

Navigation