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Published in: Pathology & Oncology Research 3/2018

01-07-2018 | Original Article

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

Authors: Constantinos Giaginis, Anastasia Sampani, Iolly Kotta-Loizou, Ioanna Giannopoulou, Eugene Danas, Ekaterini Politi, Gerasimos Tsourouflis, Gregorios Kouraklis, Efstratios Patsouris, Antonios Keramopoulos, Lydia Nakopoulou, Stamatios Theocharis

Published in: Pathology & Oncology Research | Issue 3/2018

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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.
Literature
1.
go back to reference 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 271:8144–81451CrossRefPubMed 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 271:8144–81451CrossRefPubMed
2.
go back to reference Burd CG, Dreyfuss G (1994) Conserved structures and diversity of functions of RNA-binding proteins. Science 265:615–621CrossRefPubMed Burd CG, Dreyfuss G (1994) Conserved structures and diversity of functions of RNA-binding proteins. Science 265:615–621CrossRefPubMed
3.
go back to reference 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 101:2987–2992CrossRefPubMed 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 101:2987–2992CrossRefPubMed
5.
go back to reference 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 16:3087–3099CrossRefPubMedPubMedCentral 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 16:3087–3099CrossRefPubMedPubMedCentral
6.
go back to reference 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 100:8354–8359CrossRefPubMedPubMedCentral 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 100:8354–8359CrossRefPubMedPubMedCentral
7.
go back to reference Zhu H, Zhou HL, Hasman RA, Lou H (2007) Hu proteins regulate polyadenylation by blocking sites containing U-rich sequences. J Biol Chem 282:2203–2210CrossRefPubMed Zhu H, Zhou HL, Hasman RA, Lou H (2007) Hu proteins regulate polyadenylation by blocking sites containing U-rich sequences. J Biol Chem 282:2203–2210CrossRefPubMed
10.
go back to reference 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 12:1082–1093CrossRefPubMed 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 12:1082–1093CrossRefPubMed
11.
go back to reference Ghosh N, Chaki R, Mandal V, Mandal SC (2010) COX-2 as a target for cancer chemotherapy. Pharmacol Rep 62:233–244CrossRefPubMed Ghosh N, Chaki R, Mandal V, Mandal SC (2010) COX-2 as a target for cancer chemotherapy. Pharmacol Rep 62:233–244CrossRefPubMed
13.
14.
go back to reference Kos Z, Dabbs DJ (2016) Biomarker assessment and molecular testing for prognostication in breast cancer. Histopathology 68:70–85CrossRefPubMed Kos Z, Dabbs DJ (2016) Biomarker assessment and molecular testing for prognostication in breast cancer. Histopathology 68:70–85CrossRefPubMed
15.
go back to reference Kotta-Loizou I, Giaginis C, Theocharis S (2014) Clinical significance of HuR expression in human malignancy. Med Oncol 31:161CrossRefPubMed Kotta-Loizou I, Giaginis C, Theocharis S (2014) Clinical significance of HuR expression in human malignancy. Med Oncol 31:161CrossRefPubMed
16.
go back to reference 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 107:6858–6863CrossRefPubMedPubMedCentral 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 107:6858–6863CrossRefPubMedPubMedCentral
17.
go back to reference 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 180:1751–1760CrossRefPubMedPubMedCentral 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 180:1751–1760CrossRefPubMedPubMedCentral
18.
go back to reference Lopez de Silanes I, Lal A, Gorospe M (2005) HuR: post-transcriptional paths to malignancy. RNA Biol 2:11–13CrossRefPubMed Lopez de Silanes I, Lal A, Gorospe M (2005) HuR: post-transcriptional paths to malignancy. RNA Biol 2:11–13CrossRefPubMed
19.
go back to reference 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 36:315–327CrossRefPubMed 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 36:315–327CrossRefPubMed
20.
go back to reference 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 105:20297–20302CrossRefPubMedPubMedCentral 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 105:20297–20302CrossRefPubMedPubMedCentral
22.
go back to reference Srikantan S, Gorospe M (2012) HuR function in disease. Front Biosci (Landmark Ed) 17:189–205CrossRef Srikantan S, Gorospe M (2012) HuR function in disease. Front Biosci (Landmark Ed) 17:189–205CrossRef
23.
go back to reference 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 68:9469–9478CrossRefPubMed 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 68:9469–9478CrossRefPubMed
24.
go back to reference 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 10:5580–5586CrossRefPubMed 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 10:5580–5586CrossRefPubMed
25.
26.
go back to reference 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 34:2299–2308CrossRefPubMed 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 34:2299–2308CrossRefPubMed
27.
go back to reference 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 141:213–224CrossRefPubMed 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 141:213–224CrossRefPubMed
28.
go back to reference Heinonen M, Bono P, Narko K et al (2005) Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma. Cancer Res 65:2157–2161CrossRefPubMed Heinonen M, Bono P, Narko K et al (2005) Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma. Cancer Res 65:2157–2161CrossRefPubMed
29.
go back to reference Heinonen M, Fagerholm R, Aaltonen K et al (2007) Prognostic role of HuR in hereditary breast cancer. Clin Cancer Res 13:6959–6963CrossRefPubMed Heinonen M, Fagerholm R, Aaltonen K et al (2007) Prognostic role of HuR in hereditary breast cancer. Clin Cancer Res 13:6959–6963CrossRefPubMed
30.
go back to reference 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 31:303–310PubMed 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 31:303–310PubMed
31.
go back to reference 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 29:2053–2061CrossRefPubMed 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 29:2053–2061CrossRefPubMed
32.
go back to reference 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 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
33.
go back to reference 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 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
34.
go back to reference Robins P, Pinder S, de Klerk N (1995) Histological grading of breast carcinomas: a study of interobserver agreement. Hum Pathol 6:873–879CrossRef Robins P, Pinder S, de Klerk N (1995) Histological grading of breast carcinomas: a study of interobserver agreement. Hum Pathol 6:873–879CrossRef
35.
go back to reference 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 62:899–907CrossRefPubMed 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 62:899–907CrossRefPubMed
36.
go back to reference 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 16:497–507CrossRefPubMed 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 16:497–507CrossRefPubMed
37.
go back to reference 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 35:61–71CrossRefPubMed 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 35:61–71CrossRefPubMed
38.
go back to reference 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 210:533–540CrossRefPubMed 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 210:533–540CrossRefPubMed
39.
go back to reference 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 22:189–196CrossRefPubMed 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 22:189–196CrossRefPubMed
40.
go back to reference 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 28:2786–2795CrossRef 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 28:2786–2795CrossRef
41.
go back to reference 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 31:3997–3401CrossRefPubMed 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 31:3997–3401CrossRefPubMed
42.
go back to reference Nakopoulou L, Mylona E, Papadaki I et al (2005) Overexpression of cyclooxygenase-2 is associated with a favorable prognostic phenotype in breast carcinoma. Pathobiology 72:241–249CrossRefPubMed Nakopoulou L, Mylona E, Papadaki I et al (2005) Overexpression of cyclooxygenase-2 is associated with a favorable prognostic phenotype in breast carcinoma. Pathobiology 72:241–249CrossRefPubMed
Metadata
Title
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
Authors
Constantinos Giaginis
Anastasia Sampani
Iolly Kotta-Loizou
Ioanna Giannopoulou
Eugene Danas
Ekaterini Politi
Gerasimos Tsourouflis
Gregorios Kouraklis
Efstratios Patsouris
Antonios Keramopoulos
Lydia Nakopoulou
Stamatios Theocharis
Publication date
01-07-2018
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 3/2018
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-017-0288-1

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