Prognostic value of ephrin B receptors in breast cancer: An online survival analysis using the microarray data of 3,554 patients

Mu,Xin; Huang,Ou; Jiang,Min; Xie,Zuoquan; Chen,Debo; Zhang,Xi

doi:10.3892/ol.2019.10363

Prognostic value of ephrin B receptors in breast cancer: An online survival analysis using the microarray data of 3,554 patients

Authors:
- Xin Mu
- Ou Huang
- Min Jiang
- Zuoquan Xie
- Debo Chen
- Xi Zhang
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Affiliations: Department of Urology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China, Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China, Division of Anti‑tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200025, P.R. China, Department of Breast Oncology, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
Published online on: May 17, 2019 https://doi.org/10.3892/ol.2019.10363
Pages: 742-750
Copyright: © Mu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The roles of Ephrin B (EphB) receptors in cancer are relatively unknown as these receptors are associated with complex signaling pathways. A limited number of studies have investigated the association between EphB receptors and prognosis. Using the Kaplan‑Meier plotter database, the present study investigated the associations between the mRNA expression levels of five EphB receptors and the outcomes of 3,554 patients with breast cancer who had been followed‑up for 20 years. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated to assess the relative risk of survival. The results demonstrated that high mRNA expression levels of EphB2 (HR, 0.74; 95% CI, 0.66‑0.84; P=2.1x10‑6), EphB4 (HR, 0.82; 95% CI, 0.72‑0.93; P=0.0023) and EphB6 (HR, 0.69; 95% CI, 0.61‑0.78; P=3x10‑9) were significantly associated with improved survival, while a high mRNA expression level of EphB3 (HR, 1.14; 95% CI, 1.01‑1.28; P=0.029) was associated with worse survival for patients with breast cancer. High expression levels of all EphB receptors, including EphB1 (HR, 1.4; 95% CI, 1.02‑1.94; P=0.039), EphB2 (HR, 1.34; 95% CI, 1.07‑1.67; P=0.011), EphB3 (HR, 1.39; 95% CI, 1.11‑1.73, P=0.0038), EphB4 (HR, 1.33; 95% CI, 1.06‑1.67; P=0.013) and EphB6 (HR, 1.32; 95% CI, 1.05‑1.65; P=0.016), were associated with an increased risk of mortality in patients with lymph‑node‑positive breast cancer. High mRNA expression levels of EphB1 were not associated with survival for all patients with breast cancer (HR, 0.85; 95% CI, 0.72‑1.01; P=0.058). The results of the present suggested that EphB receptors may be useful as prognostic biomarkers of breast cancer.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
2	Gonzalez-Conchas GA, Rodriguez-Romo L, Hernandez-Barajas D, Gonzalez-Guerrero JF, Rodriguez-Fernandez IA, Verdines-Perez A, Templeton AJ, Ocana A, Seruga B, Tannock IF, et al: Epidermal growth factor receptor overexpression and outcomes in early breast cancer: A systematic review and a meta-analysis. Cancer Treat Rev. 62:1–8. 2018. View Article : Google Scholar : PubMed/NCBI
3	Pasquale EB: Eph-ephrin bidirectional signaling in physiology and disease. Cell. 133:38–52. 2008. View Article : Google Scholar : PubMed/NCBI
4	Himanen JP, Saha N and Nikolov DB: Cell-cell signaling via Eph receptors and ephrins. Curr Opin Cell Biol. 19:534–542. 2007. View Article : Google Scholar : PubMed/NCBI
5	Brantley-Sieders DM: Clinical relevance of Ephs and ephrins in cancer: Lessons from breast, colorectal, and lung cancer profiling. Semin Cell Dev Biol. 23:102–108. 2012. View Article : Google Scholar : PubMed/NCBI
6	Kaenel P, Mosimann M and Andres AC: The multifaceted roles of Eph/ephrin signaling in breast cancer. Cell Adh Migr. 6:138–147. 2012. View Article : Google Scholar : PubMed/NCBI
7	Genander M and Frisén J: Ephrins and Eph receptors in stem cells and cancer. Curr Opin Cell Biol. 22:611–616. 2010. View Article : Google Scholar : PubMed/NCBI
8	Lin B, Yin T, Wu YI, Inoue T and Levchenko A: Interplay between chemotaxis and contact inhibition of locomotion determines exploratory cell migration. Nat Commun. 6:66192015. View Article : Google Scholar : PubMed/NCBI
9	Pasquale EB: Eph receptors and ephrins in cancer: Bidirectional signalling and beyond. Nat Rev Cancer. 10:165–180. 2010. View Article : Google Scholar : PubMed/NCBI
10	Noren NK, Foos G, Hauser CA and Pasquale EB: The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nat Cell Biol. 8:815–825. 2006. View Article : Google Scholar : PubMed/NCBI
11	Janes PW, Griesshaber B, Atapattu L, Nievergall E, Hii LL, Mensinga A, Chheang C, Day BW, Boyd AW, Bastiaens PI, et al: Eph receptor function is modulated by heterooligomerization of A and B type Eph receptors. J Cell Biol. 195:1033–1045. 2011. View Article : Google Scholar : PubMed/NCBI
12	Arvanitis D and Davy A: Eph/ephrin signaling: Networks. Genes Dev. 22:416–429. 2008. View Article : Google Scholar : PubMed/NCBI
13	Cortina C, Palomo-Ponce S, Iglesias M, Fernández-Masip JL, Vivancos A, Whissell G, Humà M, Peiró N, Gallego L, Jonkheer S, et al: EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells. Nat Genet. 39:1376–1383. 2007. View Article : Google Scholar : PubMed/NCBI
14	Győrffy B, Surowiak P, Budczies J and Lánczky A: Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One. 8:e822412013. View Article : Google Scholar : PubMed/NCBI
15	Pénzváltó Z, Lánczky A, Lénárt J, Meggyesházi N, Krenács T, Szoboszlai N, Denkert C, Pete I and Győrffy B: MEK1 is associated with carboplatin resistance and is a prognostic biomarker in epithelial ovarian cancer. BMC Cancer. 14:8372014. View Article : Google Scholar : PubMed/NCBI
16	Győrffy B, Bottai G, Lehmann-Che J, Kéri G, Orfi L, Iwamoto T, Desmedt C, Bianchini G, Turner NC, de Thè H, et al: TP53 mutation-correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53-mutated breast cancers. Mol Oncol. 8:508–519. 2014. View Article : Google Scholar : PubMed/NCBI
17	Pongor L, Kormos M, Hatzis C, Pusztai L, Szabó A and Győrffy B: A genome-wide approach to link genotype to clinical outcome by utilizing next generation sequencing and gene chip data of 6,697 breast cancer patients. Genome Med. 7:1042015. View Article : Google Scholar : PubMed/NCBI
18	Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q and Szallasi Z: An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 123:725–731. 2010. View Article : Google Scholar : PubMed/NCBI
19	Gyorffy B, Lánczky A and Szállási Z: Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer. 19:197–208. 2012. View Article : Google Scholar : PubMed/NCBI
20	Bonifaci N, Górski B, Masojć B, Wokołorczyk D, Jakubowska A, Dębniak T, Berenguer A, Serra Musach J, Brunet J, Dopazo J, et al: Exploring the link between germline and somatic genetic alterations in breast carcinogenesis. PLoS One. 5:e140782010. View Article : Google Scholar : PubMed/NCBI
21	Becker E, Huynh-Do U, Holland S, Pawson T, Daniel TO and Skolnik EY: Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation. Mol Cell Biol. 20:1537–1545. 2000. View Article : Google Scholar : PubMed/NCBI
22	Stein E, Huynh-Do U, Lane AA, Cerretti DP and Daniel TO: Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase. J Biol Chem. 273:1303–1308. 1998. View Article : Google Scholar : PubMed/NCBI
23	Vindis C, Cerretti DP, Daniel TO and Huynh-Do U: EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis. J Cell Biol. 162:661–671. 2003. View Article : Google Scholar : PubMed/NCBI
24	Chukkapalli S, Amessou M, Dilly AK, Dekhil H, Zhao J, Liu Q, Bejna A, Thomas RD, Bandyopadhyay S, Bismar TA, et al: Role of the EphB2 receptor in autophagy, apoptosis and invasion in human breast cancer cells. Exp Cell Res. 320:233–246. 2014. View Article : Google Scholar : PubMed/NCBI
25	Genander M, Halford MM, Xu NJ, Eriksson M, Yu Z, Qiu Z, Martling A, Greicius G, Thakar S, Catchpole T, et al: Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell. 139:679–692. 2009. View Article : Google Scholar : PubMed/NCBI
26	Husa AM, Magić Ž, Larsson M, Fornander T and Pérez-Tenorio G: EPH/ephrin profile and EPHB2 expression predicts patient survival in breast cancer. Oncotarget. 7:21362–21380. 2016. View Article : Google Scholar : PubMed/NCBI
27	Lam S, Wiercinska E, Teunisse AF, Lodder K, ten Dijke P and Jochemsen AG: Wild-type p53 inhibits pro-invasive properties of TGF-β3 in breast cancer, in part through regulation of EPHB2, a new TGF-β target gene. Breast Cancer Res Treat. 148:7–18. 2014. View Article : Google Scholar : PubMed/NCBI
28	Poliakov A, Cotrina ML, Pasini A and Wilkinson DG: Regulation of EphB2 activation and cell repulsion by feedback control of the MAPK pathway. J Cell Biol. 183:933–947. 2008. View Article : Google Scholar : PubMed/NCBI
29	Dail M, Richter M, Godement P and Pasquale EB: Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion. J Cell Sci. 119:1244–1254. 2006. View Article : Google Scholar : PubMed/NCBI
30	Miao H, Strebhardt K, Pasquale EB, Shen TL, Guan JL and Wang B: Inhibition of integrin-mediated cell adhesion but not directional cell migration requires catalytic activity of EphB3 receptor tyrosine kinase. Role of Rho family small GTPases. J Biol Chem. 280:923–932. 2005. View Article : Google Scholar : PubMed/NCBI
31	Maddigan A, Truitt L, Arsenault R, Freywald T, Allonby O, Dean J, Narendran A, Xiang J, Weng A, Napper S and Freywald A: EphB receptors trigger Akt activation and suppress Fas receptor-induced apoptosis in malignant T lymphocytes. J Immunol. 187:5983–5994. 2011. View Article : Google Scholar : PubMed/NCBI
32	Nikolova Z, Djonov V, Zuercher G, Andres AC and Ziemiecki A: Cell-type specific and estrogen dependent expression of the receptor tyrosine kinase EphB4 and its ligand ephrin-B2 during mammary gland morphogenesis. J Cell Sci. 111:2741–2751. 1998.PubMed/NCBI
33	Munarini N, Jäger R, Abderhalden S, Zuercher G, Rohrbach V, Loercher S, Pfanner-Meyer B, Andres AC and Ziemiecki A: Altered mammary epithelial development, pattern formation and involution in transgenic mice expressing the EphB4 receptor tyrosine kinase. J Cell Sci. 115:25–37. 2002.PubMed/NCBI
34	Rutkowski R, Mertens-Walker I, Lisle JE, Herington AC and Stephenson SA: Evidence for a dual function of EphB4 as tumor promoter and suppressor regulated by the absence or presence of the ephrin-B2 ligand. Int J Cancer. 131:E614–E624. 2012. View Article : Google Scholar : PubMed/NCBI
35	Pradeep S, Huang J, Mora EM, Nick AM, Cho MS, Wu SY, Noh K, Pecot CV, Rupaimoole R, Stein MA, et al: Erythropoietin stimulates tumor growth via EphB4. Cancer Cell. 28:610–622. 2015. View Article : Google Scholar : PubMed/NCBI
36	Li X, Song C, Huang G, Sun S, Qiao J, Zhao J, Zhao Z and Li M: The coexpression of EphB4 and EphrinB2 is associated with poor prognosis in HER2-positive breast cancer. Onco Targets Ther. 10:1735–1742. 2017. View Article : Google Scholar : PubMed/NCBI
37	Brantley-Sieders DM, Jiang A, Sarma K, Badu-Nkansah A, Walter DL, Shyr Y and Chen J: Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome. PLoS One. 6:e244262011. View Article : Google Scholar : PubMed/NCBI
38	Barneh F, Moshayedi M, Mirmohammadsadeghi H, Haghjooy-Javanmard S, Sabzghabaee AM and Badri S: EphB4 tyrosine kinase stimulation inhibits growth of MDA-MB-231 breast cancer cells in a dose and time dependent manner. Dis Markers. 35:933–938. 2013. View Article : Google Scholar : PubMed/NCBI
39	Noren NK and Pasquale EB: Paradoxes of the EphB4 receptor in cancer. Cancer Res. 67:3994–3997. 2007. View Article : Google Scholar : PubMed/NCBI
40	Steinle JJ, Meininger CJ, Forough R, Wu G, Wu MH and Granger HJ: Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. J Biol Chem. 277:43830–43835. 2002. View Article : Google Scholar : PubMed/NCBI
41	Truitt L, Freywald T, DeCoteau J, Sharfe N and Freywald A: The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells. Cancer Res. 70:1141–1153. 2010. View Article : Google Scholar : PubMed/NCBI
42	Bhushan L, Tavitian N, Dey D, Tumur Z, Parsa C and Kandpal RP: Modulation of liver-intestine cadherin (Cadherin 17) expression, ERK phosphorylation and WNT signaling in EPHB6 receptor-expressing MDA-MB-231 cells. Cancer Genomics Proteomics. 11:239–249. 2014.PubMed/NCBI
43	Fox BP and Kandpal RP: EphB6 receptor significantly alters invasiveness and other phenotypic characteristics of human breast carcinoma cells. Oncogene. 28:1706–1713. 2009. View Article : Google Scholar : PubMed/NCBI
44	Kandpal RP: Tyrosine kinase-deficient EphB6 receptor-dependent alterations in proteomic profiles of invasive breast carcinoma cells as determined by difference gel electrophoresis. Cancer Genomics Proteomics. 7:253–260. 2010.PubMed/NCBI
45	Moshayedi M, Barneh F, Haghjooy-Javanmard S, Sadeghi HM, Eskandari N and Sabzghabaee AM: A rapid and sensitive method for EphB4 identification as a diagnostic and therapeutic biomarker in invasive breast cancer. J Cancer Res Ther. 12:188–192. 2016. View Article : Google Scholar : PubMed/NCBI
46	Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, et al: The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 486:346–352. 2012. View Article : Google Scholar : PubMed/NCBI
47	Pereira B, Chin SF, Rueda OM, Vollan HK, Provenzano E, Bardwell HA, Pugh M, Jones L, Russell R, Sammut S, et al: The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun. 7:114792016. View Article : Google Scholar : PubMed/NCBI
48	Kullander K and Klein R: Mechanisms and functions of Eph and ephrin signalling. Nat Rev Mol Cell Biol. 3:475–486. 2002. View Article : Google Scholar : PubMed/NCBI
49	Fox BP and Kandpal RP: A paradigm shift in EPH receptor interaction: Biological relevance of EPHB6 interaction with EPHA2 and EPHB2 in breast carcinoma cell lines. Cancer Genomics Proteomics. 8:185–193. 2011.PubMed/NCBI
50	Klein R: Bidirectional modulation of synaptic functions by Eph/ephrin signaling. Nat Neurosci. 12:15–20. 2009. View Article : Google Scholar : PubMed/NCBI
51	Orsulic S and Kemler R: Expression of Eph receptors and ephrins is differentially regulated by E-cadherin. J Cell Sci. 113:1793–1802. 2000.PubMed/NCBI
52	Paul JM, Toosi B, Vizeacoumar FS, Bhanumathy KK, Li Y, Gerger C, El Zawily A, Freywald T, Anderson DH, Mousseau D, et al: Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment. Oncotarget. 7:50027–50042. 2016. View Article : Google Scholar : PubMed/NCBI
53	Lodola A, Giorgio C, Incerti M, Zanotti I and Tognolini M: Targeting Eph/ephrin system in cancer therapy. Eur J Med Chem. 142:152–162. 2017. View Article : Google Scholar : PubMed/NCBI
54	Chrencik JE, Brooun A, Recht MI, Nicola G, Davis LK, Abagyan R, Widmer H, Pasquale EB and Kuhn P: Three-dimensional structure of the EphB2 receptor in complex with an antagonistic peptide reveals a novel mode of inhibition. J Biol Chem. 282:36505–36513. 2007. View Article : Google Scholar : PubMed/NCBI
55	Koolpe M, Burgess R, Dail M and Pasquale EB: EphB receptor-binding peptides identified by phage display enable design of an antagonist with ephrin-like affinity. J Biol Chem. 280:17301–17311. 2005. View Article : Google Scholar : PubMed/NCBI