Human Pathology
Volume 41, Issue 1 , Pages 48-58 , January 2010

Frequent epigenetic inactivation of the receptor tyrosine kinase EphA5 by promoter methylation in human breast cancer

  • De-Yuan Fu, MD

      Affiliations

    • Breast Cancer Institute, Cancer Hospital, Department of Oncology, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, Shanghai 200032, PR China
    • Department of Breast Surgery, Subei People's Hospital of Jiangsu Province, Yangzhou, 225001, China
    • These authors contributed equally to this work.
    • ,
  • Zhi-Min Wang, PhD

      Affiliations

    • Chinese National Human Genome Center at Shanghai, Shanghai, 201203, PR China
    • These authors contributed equally to this work.
    • ,
  • Bei-Lan Wang, BS

      Affiliations

    • Chinese National Human Genome Center at Shanghai, Shanghai, 201203, PR China
    • ,
  • Li Chen, MS

      Affiliations

    • Breast Cancer Institute, Cancer Hospital, Department of Oncology, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, Shanghai 200032, PR China
    • ,
  • Wen-Tao Yang, MD

      Affiliations

    • Department of Pathology, Cancer Hospital, Department of Oncology, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, Shanghai 200032, PR China
    • ,
  • Zhen-Zhou Shen, MD

      Affiliations

    • Breast Cancer Institute, Cancer Hospital, Department of Oncology, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, Shanghai 200032, PR China
    • ,
  • Wei Huang, PhD

      Affiliations

    • Chinese National Human Genome Center at Shanghai, Shanghai, 201203, PR China
    • Corresponding Author InformationCorresponding authors. Zhi-Min Shao is to be contacted at Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, Shanghai 200032, PR China. Wei Huang, Chinese National Human Genome Center at Shanghai, Shanghai 201203, PR China.
    • ,
  • Zhi-Ming Shao, MD

      Affiliations

    • Breast Cancer Institute, Cancer Hospital, Department of Oncology, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, Shanghai 200032, PR China
    • Corresponding Author InformationCorresponding authors. Zhi-Min Shao is to be contacted at Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, Shanghai 200032, PR China. Wei Huang, Chinese National Human Genome Center at Shanghai, Shanghai 201203, PR China.

Received 10 March 2009 ,Revised 3 June 2009 ,Accepted 11 June 2009.

References 

  1. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–2054
  2. Das PM, Singal R. DNA methylation and cancer. J Clin Oncol. 2004;22:4632–4642
  3. Szyf M, Pakneshan P, Rabbani SA. DNA methylation and breast cancer. Biochem Pharmacol. 2004;68:1187–1197
  4. Kullander K, Klein R. Mechanisms and functions of Eph and ephrin signaling. Nat Rev Mol Cell Biol. 2002;3:475–486
  5. Holmberg J, Clarke DL, Frisén J. Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature. 2000;408:203–206
  6. Merlos-Suárez A, Batlle E. Eph-ephrin signalling in adult tissues and cancer. Curr Opin Cell Biol. 2008;20:194–200
  7. Liu W, Ahmad SA, Jung YD, et al. Coexpression of ephrin-Bs and their receptors in colon carcinoma. Cancer. 2002;94:934–939
  8. Kinch MS, Moore MB, Harpole DH. Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival. Clin Cancer Res. 2003;9:613–618
  9. Walker-Daniels J, Coffman K, Azimi M, et al. Overexpression of the EphA2 tyrosine kinase in prostate cancer. Prostate. 1999;41:275–280
  10. Andres AC, Reid HH, Zürcher G, et al. Expression of two novel eph-related receptor protein tyrosine kinases in mammary gland development and carcinogenesis. Oncogene. 1994;9:1461–1467
  11. Noren NK, Foos G, Hauser CA, et al. The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nat Cell Biol. 2006;8:815–825
  12. Fang WB, Brantley-Sieders DM, Parker MA, et al. A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis. Oncogene. 2005;24:7859–7868
  13. Ireton RC, Chen J. EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Curr Cancer Drug Targets. 2005;5:149–157
  14. Fox BP, Kandpal RP. Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application. Biochem Biophys Res Commun. 2004;318:882–892
  15. Brantley-Sieders DM, Zhuang G, Hicks D, et al. The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling. J Clin Invest. 2008;118:64–78
  16. Lu M, Miller KD, Gokmen-Polar Y, et al. EphA2 overexpression decreases estrogen dependence and tamoxifen sensitivity. Cancer Res. 2003;63:3425–3429
  17. Dottori M, Down M, Hüttmann A, et al. Cloning and characterization of EphA3 (Hek) gene promoter: DNA methylation regulates expression in hematopoietic tumor cells. Blood. 1999;94:2477–2486
  18. Wang J, Kataoka H, Suzuki M, et al. Downregulation of EphA7 by hypermethylation in colorectal cancer. Oncogene. 2005;24:5637–5647
  19. Wang J, Li G, Ma H, Bao Y, et al. Differential expression of EphA7 receptor tyrosine kinase in gastric carcinoma. Hum Pathol. 2007;38:1649–1656
  20. Dawson DW, Hong JS, Shen RR, et al. Global DNA methylation profiling reveals silencing of a secreted form of Epha7 in mouse and human germinal center B-cell lymphomas. Oncogene. 2007;26:4243–4252
  21. Fox BP, Kandpal RP. Transcriptional silencing of EphB6 receptor tyrosine kinase in invasive breast carcinoma cells and detection of methylated promoter by methylation specific PCR. Biochem Biophys Res Commun. 2006;340:268–276
  22. Yue Y, Chen ZY, Gale NW, et al. Mistargeting hippocampal axons by expression of a truncated Eph receptor. Proc Natl Acad Sci U S A. 2002;99:10777–10782
  23. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer: I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19:403–410
  24. Molino A, Micciolo R, Turazza M, et al. Estrogen receptors in 699 primary breast cancers: a comparison of immunohistochemical and biochemical methods. Breast Cancer Res Treat. 1995;34:221–228
  25. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118–145
  26. Feltus FA, Lee EK, Costello JF, et al. Predicting aberrant CpG island methylation. Proc Natl Acad Sci U S A. 2003;100:12253–12258
  27. Matros E, Wang ZC, Lodeiro G, et al. BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles. Breast Cancer Res Treat. 2005;91:179–186
  28. Holst CR, Nuovo GJ, Esteller M, et al. Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia. Cancer Res. 2003;63:1596–1601
  29. Nass SJ, Herman JG, Gabrielson E, et al. Aberrant methylation of the estrogen receptor and E-cadherin 5′ CpG islands increases with malignant progression in human breast cancer. Cancer Res. 2000;60:4346–4348
  30. Ottaviano YL, Issa JP, Parl FF, et al. Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res. 1994;54:2552–2555
  31. Fackler MJ, McVeigh M, Evron E, et al. DNA methylation of RASSF1A, HIN-1, RAR-beta, Cyclin D2 and Twist in in situ and invasive lobular breast carcinoma. Int J Cancer. 2003;107:970–975
  32. Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer. 1989;63:181–187
  33. Lehmann U, Langer F, Feist H, et al. Quantitative assessment of promoter hypermethylation during breast cancer development. Am J Pathol. 2002;160:605–612

☆ This research was supported in part by the grants from the National Basic Research Program of China (2006CB910501), National Natural Science Foundation of China (30371580, 30572109), and Shanghai Science and Technology Committee (03J14019, 06DJ14004, 06DZ19504).

PII: S0046-8177(09)00226-3

doi: 10.1016/j.humpath.2009.06.007

Human Pathology
Volume 41, Issue 1 , Pages 48-58 , January 2010

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