BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Prognostic role of EGR1 in breast cancer: a systematic review

  • Saha, Subbroto Kumar (Department of Stem Cell and Regenerative Biotechnology, Konkuk University) ;
  • Islam, S.M. Riazul (Department of Computer Science and Engineering, Sejong University) ;
  • Saha, Tripti (Department of Stem Cell and Regenerative Biotechnology, Konkuk University) ;
  • Nishat, Afsana (Department of Microbiology & Cell Science, University of Florida) ;
  • Biswas, Polash Kumar (Department of Stem Cell and Regenerative Biotechnology, Konkuk University) ;
  • Gil, Minchan (Department of Stem Cell and Regenerative Biotechnology, Konkuk University) ;
  • Nkenyereye, Lewis (Department of Computer and Information Security, Sejong University) ;
  • El-Sappagh, Shaker (Centro Singular de Investigacion en Tecnoloxías Intelixentes (CiTIUS), Universidade de Santiago de Compostela) ;
  • Islam, Md. Saiful (School of Information and Communication Technology, Griffith University) ;
  • Cho, Ssang-Goo (Department of Stem Cell and Regenerative Biotechnology, Konkuk University)
  • Received : 2021.07.07
  • Accepted : 2021.08.16
  • Published : 2021.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

EGR1 (early growth response 1) is dysregulated in many cancers and exhibits both tumor suppressor and promoter activities, making it an appealing target for cancer therapy. Here, we used a systematic multi-omics analysis to review the expression of EGR1 and its role in regulating clinical outcomes in breast cancer (BC). EGR1 expression, its promoter methylation, and protein expression pattern were assessed using various publicly available tools. COSMIC-based somatic mutations and cBioPortal-based copy number alterations were analyzed, and the prognostic roles of EGR1 in BC were determined using Prognoscan and Kaplan-Meier Plotter. We also used bc-GenEx-Miner to investigate the EGR1 co-expression profile. EGR1 was more often downregulated in BC tissues than in normal breast tissue, and its knockdown was positively correlated with poor survival. Low EGR1 expression levels were also associated with increased risk of ER+, PR+, and HER2- BCs. High positive correlations were observed among EGR1, DUSP1, FOS, FOSB, CYR61, and JUN mRNA expression in BC tissue. This systematic review suggested that EGR1 expression may serve as a prognostic marker for BC patients and that clinicopathological parameters influence its prognostic utility. In addition to EGR1, DUSP1, FOS, FOSB, CYR61, and JUN can jointly be considered prognostic indicators for BC.

Keywords

Acknowledgement

This study was supported by grants from the National Research Foundation (NRF) funded by the Korean government (grant no. 2015R1A5A1009701 and 2019M3A9H1030682); and, in part by the National Research Foundation of Korea-Grant funded by the Korean Government (Ministry of Science and ICT)-NRF-2017R1A2B2012337. In addition, this paper was written as part of Konkuk University's research support program for its faculty on sabbatical leave in 2019-2020.

References

  1. Shah R, Rosso K and Nathanson SD (2014) Pathogenesis, prevention, diagnosis and treatment of breast cancer. World J Clin Oncol 5, 283-298 https://doi.org/10.5306/wjco.v5.i3.283
  2. Ataollahi MR, Sharifi J, Paknahad MR and Paknahad A (2015) Breast cancer and associated factors: a review. J Med Life 8 (Spec Iss 4), 6-11
  3. Nunziato M, Esposito MV, Starnone F et al (2019) A multigene panel beyond BRCA1/BRCA2 to identify new breast cancer-predisposing mutations by a picodroplet PCR followed by a next-generation sequencing strategy: a pilot study. Anal Chim Acta 1046, 154-162 https://doi.org/10.1016/j.aca.2018.09.032
  4. Blaschke F, Bruemmer D and Law RE (2004) Egr-1 is a major vascular pathogenic transcription factor in atherosclerosis and restenosis. Rev Endocr Metab Dis 5, 249-254 https://doi.org/10.1023/B:REMD.0000032413.88756.ee
  5. Myung DS, Park YL, Kim N et al (2014) Expression of early growth response-1 in colorectal cancer and its relation to tumor cell proliferation and apoptosis. Oncol Rep 31, 788-794 https://doi.org/10.3892/or.2013.2884
  6. Ma Z, Gao X, Shuai Y et al (2021) EGR1-mediated linc01503 promotes cell cycle progression and tumorigenesis in gastric cancer. Cell Proliferation 54, e12922 https://doi.org/10.1111/cpr.12922
  7. Zhao J, Li H and Yuan M (2021) EGR1 promotes stemness and predicts a poor outcome of uterine cervical cancer by inducing SOX9 expression. Genes Genomics 43, 459-470 https://doi.org/10.1007/s13258-021-01064-5
  8. Ma S, Cheng J, Wang H et al (2021) A novel regulatory loop miR-101/ANXA2/EGR1 mediates malignant characteristics of liver cancer stem cells. Carcinogenesis 42, 93-104 https://doi.org/10.1093/carcin/bgaa055
  9. Mohamad T, Kazim N, Adhikari A, Davie JK (2018) EGR1 interacts with TBX2 and functions as a tumor suppressor in rhabdomyosarcoma. Oncotarget 9, 18084-18098 https://doi.org/10.18632/oncotarget.24726
  10. Wei LL, Wu XJ, Gong CC and Pei DS (2017) Egr-1 suppresses breast cancer cells proliferation by arresting cell cycle progression via down-regulating CyclinDs. Int J Clin Exp Patho 10, 10212-10222
  11. Baron V, Adamson ED, Calogero A, Ragona G and Mercola D (2006) The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFbeta1, PTEN, p53, and fibronectin. Cancer Gene Ther 13, 115-124 https://doi.org/10.1038/sj.cgt.7700896
  12. Ferraro B, Bepler G, Sharma S, Cantor A and Haura EB (2005) EGR1 predicts PTEN and survival in patients with non-small-cell lung cancer. J Clin Oncol 23, 1921-1926 https://doi.org/10.1200/JCO.2005.08.127
  13. Zhang HH, Chen XJ, and Wang JK et al (2014) EGR1 decreases the malignancy of human non-small cell lung carcinoma by regulating KRT18 expression. Sci Rep 4, 5416 https://doi.org/10.1038/srep05416
  14. Min IM, Pietramaggiori G, Kim FS, Passegue E, Stevenson KE and Wagers AJ (2008) The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells. Cell Stem Cell 2, 380-391 https://doi.org/10.1016/j.stem.2008.01.015
  15. Chen DG, Zhu B, Lv SQl et al (2017) Inhibition of EGR1 inhibits glioma proliferation by targeting CCND1 promoter. J Exp Clin Canc Res 36, 186 https://doi.org/10.1186/s13046-017-0656-4
  16. Tao WW, Shi JF, Zhang Q, Xue B, Sun YJ and Li CJ (2013) Egr-1 enhances drug resistance of breast cancer by modulating MDR1 expression in a GGPPS-independent manner. Biomed Pharmacother 67, 197-202 https://doi.org/10.1016/j.biopha.2013.01.001
  17. Wong KM, Song J and Wong YH (2021) CTCF and EGR1 suppress breast cancer cell migration through transcriptional control of Nm23-H1. Sci Rep 11, 491 https://doi.org/10.1038/s41598-020-79869-9
  18. Hao L, Huang F, Yu X et al (2021) The role of early growth response family members 1-4 in prognostic value of breast cancer. Front Genet 12, 809
  19. Shajahan-Haq AN, Boca SM, Jin L et al (2017) EGR1 regulates cellular metabolism and survival in endocrine resistant breast cancer. Oncotarget 8, 96865-96884 https://doi.org/10.18632/oncotarget.18292
  20. Rhodes DR, Kalyana-Sundaram S, Mahavisno V et al (2007) Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9, 166-180 https://doi.org/10.1593/neo.07112
  21. Rhodes DR, Yu J, Shanker K et al (2004) ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6, 1-6 https://doi.org/10.1016/s1476-5586(04)80047-2
  22. Saha SK, Jeong Y, Cho S and Cho SG (2018) Systematic expression alteration analysis of master reprogramming factor OCT4 and its three pseudogenes in human cancer and their prognostic outcomes. Sci Rep 8, 14806 https://doi.org/10.1038/s41598-018-33094-7
  23. Saha SK, Kim KE, Islam SMR, Cho SG and Gil M (2019) Systematic multiomics analysis of alterations in C1QBP mRNA expression and relevance for clinical outcomes in cancers. J Clin Med 8, 513 https://doi.org/10.3390/jcm8040513
  24. Chandrashekar DS, Bashel B, Balasubramanya SAH et al (2017) UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 19, 649-658 https://doi.org/10.1016/j.neo.2017.05.002
  25. Goldman MJ, Craft B, Hastie M et al (2020) Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol 38, 675-678 https://doi.org/10.1038/s41587-020-0546-8
  26. Uhlen M, Zhang C, Lee S et al (2017) A pathology atlas of the human cancer transcriptome. Science 357, eaan2507 https://doi.org/10.1126/science.aan2507
  27. Uhlen M, Fagerberg L, Hallstrom BM et al (2015) Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 https://doi.org/10.1126/science.1260419
  28. Crowe AR and Yue W (2019) Semi-quantitative determination of protein expression using immunohistochemistry staining and analysis: an integrated protocol. Bio Protoc 9, e3465
  29. Diez-Villanueva A, Mallona I and Peinado MA (2015) Wanderer, an interactive viewer to explore DNA methylation and gene expression data in human cancer. Epigenetics Chromatin 8, 22 https://doi.org/10.1186/s13072-015-0014-8
  30. Saha SK, Islam S, Abdullah-AL-Wadud M, Islam S, Ali F and Park KS (2019) Multiomics analysis reveals that GLS and GLS2 differentially modulate the clinical outcomes of cancer. J Clin Med 8, 355 https://doi.org/10.3390/jcm8030355
  31. Tate JG, Bamford S, Jubb HC et al (2019) COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res 47, D941-D947 https://doi.org/10.1093/nar/gky1015
  32. Cerami E, Gao J, Dogrusoz U et al (2012) The cBio cancer genomics portal: an open platform for exploring multi-dimensional cancer genomics data. Cancer Discov 2, 401-404 https://doi.org/10.1158/2159-8290.CD-12-0095
  33. Gao J, Aksoy BA, Dogrusoz U et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6, p11
  34. Mizuno H, Kitada K, Nakai K and Sarai A (2009) Progno-Scan: a new database for meta-analysis of the prognostic value of genes. BMC Med Genomics 2, 18 https://doi.org/10.1186/1755-8794-2-18
  35. Nagy A, Lanczky A, Menyhart O and Gyorffy B (2018) Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep 8, 9227 https://doi.org/10.1038/s41598-018-27521-y
  36. Goldman M, Craft B, Hastie M, Repecka K, Kamath A, McDade F (2019) The UCSC Xena platform for cancer genomics data visualization and interpretation. BioRxiv 326470, doi: https://doi.org/10.1101/326470
  37. Jezequel P, Frenel JS, Campion L et al (2013) bc-GenEx-Miner 3.0: new mining module computes breast cancer gene expression correlation analyses. Database 2013, bas060 https://doi.org/10.1093/database/bas060
  38. Havis E and Duprez D (2020) EGR1 transcription factor is a multifaceted regulator of matrix production in tendons and other connective tissues. Int J Mol Sci 21, 1664 https://doi.org/10.3390/ijms21051664
  39. Magee N and Zhang Y (2017) Role of early growth response 1 in liver metabolism and liver cancer. Hepatoma Res 3, 268 https://doi.org/10.20517/2394-5079.2017.36
  40. Lohoff M, Giaisi M, Kohler R, Casper B, Krammer PH and Li-Weber M (2010) Early growth response protein-1 (Egr-1) is preferentially expressed in T helper type 2 (Th2) cells and is involved in acute transcription of the Th2 cytokine interleukin-4. J Biol Chem 285, 1643-1652 https://doi.org/10.1074/jbc.M109.011585
  41. Milbrandt J (1987) A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science 238, 797-799 https://doi.org/10.1126/science.3672127
  42. Duclot F and Kabbaj M (2017) The role of early growth response 1 (EGR1) in brain plasticity and neuropsychiatric disorders. Front Behav Neurosci 11, 35 https://doi.org/10.3389/fnbeh.2017.00035
  43. Thiel G and Cibelli G (2002) Regulation of life and death by the zinc finger transcription factor Egr-1. J Cell Physiol 193, 287-292 https://doi.org/10.1002/jcp.10178
  44. Egerod FL, Bartels A, Fristrup N et al (2009) High frequency of tumor cells with nuclear Egr-1 protein expression in human bladder cancer is associated with disease progression. BMC Cancer 9, 385 https://doi.org/10.1186/1471-2407-9-385
  45. Gitenay D and Baron VT (2009) Is EGR1 a potential target for prostate cancer therapy? Future Oncol 5, 993-1003 https://doi.org/10.2217/fon.09.67
  46. Lin M, Huang J, Jiang X et al (2016) A combination hepatoma-targeted therapy based on nanotechnology: pHRE-Egr1-HSV-TK/131 I-antiAFPMcAb-GCV/MFH. Sci Rep 6, 33524 https://doi.org/10.1038/srep33524
  47. Ma J, Ren Z, Ma Y et al (2009) Targeted knockdown of EGR-1 inhibits IL-8 production and IL-8-mediated invasion of prostate cancer cells through suppressing EGR-1/NF-κB synergy. J Biol Chem 284, 34600-34606 https://doi.org/10.1074/jbc.M109.016246
  48. Maegawa M, Arao T, Yokote H et al (2009) EGFR mutation up-regulates EGR1 expression through the ERK pathway. Anticancer Res 29, 1111-1117
  49. Adamson E, de Belle I, Mittal S et al (2003) Egr1 signaling in prostate cancer. Cancer Biol Ther 2, 617-622
  50. Curtis C, Shah SP, Chin S-F et al (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346-352 https://doi.org/10.1038/nature10983
  51. Liu J, Liu YG, Huang R et al (2007) Concurrent down-regulation of Egr-1 and gelsolin in the majority of human breast cancer cells. Cancer Genomics Proteomics 4, 377-385
  52. Yamashita K, Upadhyay S, Osada M et al (2002) Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. Cancer Cell 2, 485-495 https://doi.org/10.1016/S1535-6108(02)00215-5
  53. Ng JMK and Yu J (2015) Promoter hypermethylation of tumour suppressor genes as potential biomarkers in colorectal cancer. Int J Mol Sci 16, 2472-2496 https://doi.org/10.3390/ijms16022472
  54. Richter AM, Walesch SK and Dammann RH (2016) Aberrant promoter methylation of the tumour suppressor RASSF10 and its growth inhibitory function in breast cancer. Cancers 8, 26 https://doi.org/10.3390/cancers8030026
  55. Martincorena I and Campbell PJ (2015) Somatic mutation in cancer and normal cells. Science 349, 1483-1489 https://doi.org/10.1126/science.aab4082
  56. Myung E, Park YL, Kim N et al (2013) Expression of early growth response-1 in human gastric cancer and its relationship with tumor cell behaviors and prognosis. Pathol Res Pract 209, 692-699 https://doi.org/10.1016/j.prp.2013.08.001
  57. Kataoka F, Tsuda H, Arao T et al (2012) EGRI and FOSB gene expressions in cancer stroma are independent prognostic indicators for epithelial ovarian cancer receiving standard therapy. Genes Chromosomes Cancer 51, 300-312 https://doi.org/10.1002/gcc.21916
  58. Boulding T, Wu F, McCuaig R et al (2016) Differential roles for DUSP family members in epithelial-to-mesenchymal transition and cancer stem cell regulation in breast cancer. PLoS One 11, e0148065 https://doi.org/10.1371/journal.pone.0148065
  59. Chen FM, Chang HW, Yang SF et al (2012) The mitogen-activated protein kinase phosphatase-1 (MKP-1) gene is a potential methylation biomarker for malignancy of breast cancer. Exp Mol Med 44, 356-362 https://doi.org/10.3858/emm.2012.44.5.040
  60. Shen Q and Brown PH (2003) Novel agents for the prevention of breast cancer: targeting transcription factors and signal transduction pathways. J Mammary Gland Biol Neoplasia 8, 45-73 https://doi.org/10.1023/A:1025783221557
  61. Wagstaff SC, Bowler WB, Gallagher JA and Hipskind RA (2000) Extracellular ATP activates multiple signalling pathways and potentiates growth factor-induced c-fos gene expression in MCF-7 breast cancer cells. Carcinogenesis 21, 2175-2181 https://doi.org/10.1093/carcin/21.12.2175
  62. Fisler DA, Sikaria D, Yavorski JM, Tu YPN and Blanck G (2018) Elucidating feed-forward apoptosis signatures in breast cancer datasets: Higher FOS expression associated with a better outcome. Oncol Lett 16, 2757-2763
  63. Shen JL, Zhang YP, Yu H et al (2016) Role of DUSP1/MKP1 in tumorigenesis, tumor progression and therapy. Cancer Med 5, 2061-2068 https://doi.org/10.1002/cam4.772
  64. Fang J, Ye ZM, Gu FY et al (2018) DUSP1 enhances the chemoresistance of gallbladder cancer via the modulation of the p38 pathway and DNA damage/repair system. Oncol Lett 16, 1869-1875
  65. Lu CH, Shen Q, DuPre E, Kim H, Hilsenbeck S and Brown PH (2005) cFos is critical for MCF-7 breast cancer cell growth. Oncogene 24, 6516-6524 https://doi.org/10.1038/sj.onc.1208905
  66. Langer S, Singer CF, Hudelist G et al (2006) Jun and Fos family protein expression in human breast cancer: Correlation of protein expression and clinicopathological parameters. Eur J Gynaecol Oncol 27, 345-352
  67. Park JA, Na HH, Jin HO and Kim KC (2019) Increased expression of fosb through reactive oxygen species accumulation functions as pro-apoptotic protein in Piperlongumine Treated MCF7 breast cancer cells. Mol Cells 42, 884-892 https://doi.org/10.14348/molcells.2019.0088
  68. Huang Y-T, Lan Q, Lorusso G, Duffey N and Ruegg C (2017) The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis. Oncotarget 8, 9200-9215 https://doi.org/10.18632/oncotarget.13677
  69. Hellinger JW, Huchel S, Goetz L, Bauerschmitz G, Emons G and Grundker C (2019) Inhibition of CYR61-S100A4 axis limits breast cancer invasion. Front Oncol 9, 1074 https://doi.org/10.3389/fonc.2019.01074