Skip to main content
SpringerLink
Log in

Silencing of estrogen receptor α (ERα) gene by promoter hypermethylation is a frequent event in Chinese women with sporadic breast cancer

Breast Cancer Research and Treatment volume 117, pages 253–259 (2009)Cite this article

Abstract

Usually, the function of estrogen receptor alpha (ERα) could be silenced by ERα gene promoter hypermethylation. However, frequency of ERα promoter methylation and the clinicopathological characteristics of ERα methylation in Chinese women with sporadic breast cancer are unknown. The aim of this study was to determine the methylation status of ERα promoter and its possible correlation with clinicopathological features in a series of 138 sporadic breast cancers in Chinese women. ER1, ER3, ER4, and ER5 primers were used for methylation-specific polymerase chain reaction (MSP) to analyze the CpG methylation of promoter region of ERα gene. In general, we found that ERα was methylated in 60.1% (83/138) tumors, including 57 of 69 ERα negative tumors (82.6%, P < 0.00001). Specifically within each region the methylation percentage of ER1, ER3, ER4 and ER5 were 34.8%, 35.5%, 39.1%, and 36.9% respectively. The degree of methylation at four CpG sites was higher in breast cancer compared with benign breast hyperplasia (P < 0.00001). In addition, the levels of ERα protein expression diminished with the frequency of ERα methylation (P < 0.0001, r = −0.469), the probability of methylation was increased for cases with ERα and PgR negativity (P < 0.00001). Our preliminary findings demonstrate, for what we believe to be the first time, that ERα methylation occurs in high frequency and is one of the mechanisms of ERα expression silence in a subset of sporadic breast cancers from Chinese women. Epigenetic alteration of the ERα gene may play an important role in the pathogenesis of breast cancer.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. Walker RA (1999) Oestrogen receptor and its potential role in breast cancer development. J Pathol 188(3):229–230. doi:10.1002/(SICI)1096-9896(199907)188

    Article  PubMed  CAS  Google Scholar 

  2. Keen JC, Davidson NE (2003) The biology of breast carcinoma. Cancer 97(3(Suppl)):825–833. doi:10.1002/cncr.11126

    Article  PubMed  Google Scholar 

  3. Hortobagyi GN (1998) Treatment of breast cancer. N Engl J Med 339(14):974–984. doi:10.1056/NEJM199810013391407

    Article  PubMed  CAS  Google Scholar 

  4. Pinzone JJ, Stevenson H, Strobl JS, Berg PE (2004) Molecular and cellular determinants of estrogen receptor alpha expression. Mol Cell Biol 24(11):4605–4612. doi:10.1128/MCB.24.11.4605-4612.2004

    Article  PubMed  CAS  Google Scholar 

  5. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093

    Article  PubMed  CAS  Google Scholar 

  6. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K et al (2006) Race, breast cancer subtypes, and survival in the carolina breast cancer study. JAMA 295(21):2492–2502. doi:10.1001/jama.295.21.2492

    Article  PubMed  CAS  Google Scholar 

  7. Asch BB, Barcellos-Hoff MH (2000) Epigenetics and breast cancer. J Mammary Gland Biol Neoplasia 6(2):151–152. doi:10.1023/A:1011306222533

    Article  Google Scholar 

  8. Giacinti L, Claudio PP, Lopez M, Giordano A (2006) Epigenetic information and estrogen receptor alpha expression in breast cancer. Oncologist 11(1):1–8. doi:10.1634/theoncologist.11-1-1

    Article  PubMed  CAS  Google Scholar 

  9. Lapidus RG, Ferguson AT, Ottaviano YL, Parl FF, Smith HS, Weitzman SA et al (1996) Methylation of estrogen and progesterone receptor gene 5′ CpG islands correlates with lack of estrogen and progesterone receptor gene expression in breast tumors. Clin Cancer Res 2(5):805–810

    PubMed  CAS  Google Scholar 

  10. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93(18):9821–9826. doi:10.1073/pnas.93.18.9821

    Article  PubMed  CAS  Google Scholar 

  11. Lapidus RG, Nass SJ, Butash KA, Parl FF, Weitzman SA, Graff JG et al (1998) Mapping of ER gene CpG island methylation-specific polymerase chain reaction. Cancer Res 58(12):2515–2519

    PubMed  CAS  Google Scholar 

  12. Speirs V, Skliris GP, Burdall SE, Carder PJ (2002) Distinct expression patterns of ERα and ERβ in normal human mammary gland. J Clin Pathol 55(5):371–374

    PubMed  CAS  Google Scholar 

  13. Widschwendter M, Jones PA (2002) The potential prognostic, predictive, and therapeutic values of DNA methylation in cancer. Clin Cancer Res 8(1):17–21

    PubMed  Google Scholar 

  14. Szyf M, Paknesham P, Rabbani SA (2004) DNA methylation and breast cancer. Biochem Pharmacol 68(6):1187–1197. doi:10.1016/j.bcp.2004.04.030

    Article  PubMed  CAS  Google Scholar 

  15. Widschwendter M, Jones PA (2002) DNA methylation and breast carcinogenesis. Oncogene 21(35):5462–5482. doi:10.1038/sj.onc.1205606

    Article  PubMed  CAS  Google Scholar 

  16. Li S, Rong M, Iacopetta B (2006) DNA hypermethylation in breast cancer and its association with clinicopathological features. Cancer Lett 237(2):272–280. doi:10.1016/j.canlet.2005.06.011

    Article  PubMed  CAS  Google Scholar 

  17. Kos M, Reid G, Denger S, Gannon F (2001) Minireview: genomic organization of the human ER alpha gene promoter region. Mol Endocrinol 15(12):2057–2063. doi:10.1210/me.15.12.2057

    Article  PubMed  CAS  Google Scholar 

  18. Mirza S, Sharma G, Prasad CP, Parshad R, Srivastava A, Gupta SD et al (2007) Promoter hypermethylation of TMS1, BRCA1, ERα and PRB in serum and tumor DNA of invasive ductal breast carcinoma patients. Life Sci 81(4):280–287. doi:10.1016/j.lfs.2007.05.012

    Article  PubMed  CAS  Google Scholar 

  19. Wei M, Xu J, Dignam J, Nanda R, Sveen L, Fackenthal J et al (2008) Estrogen receptor a, BRCA1, and FANCF promoter methylationoccur in distinct subsets of sporadic breast cancers. Breast Cancer Res Treat 111(1):113–120. doi:10.1007/s10549-007-9766-6

    Article  PubMed  CAS  Google Scholar 

  20. Nass SJ, Herman JG, Gabrielson E, Iversen PW, Parl FF, Davidson NE et al (2000) Aberrant methylation of the estrogen receptor and E-Cadherin 5′ CpG islands increases with malignant progression in human breast cancer. Cancer Res 60(16):4346–4348

    PubMed  CAS  Google Scholar 

  21. Costello JF, Frühwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X et al (2000) Aberrant CpG island methylation has non-random and tumour-type-specific patterns. Nat Genet 24(2):132–138. doi:10.1038/72785

    Article  PubMed  CAS  Google Scholar 

  22. Rody A, Holtrich U, Solbach C, Kourtis K, von Minckwitz G, Engels K et al (2005) Methylation of estrogen receptor β promoter correlates with loss of ER-βexpression in mammary carcinoma and is an early indication marker in premalignant lesions. Endocr Relat Cancer 12(4):903–916. doi:10.1677/erc.1.01088

    Article  PubMed  CAS  Google Scholar 

  23. Kiani J, Khan A, Khawar H, Shuaib F, Pervez S (2006) Estrogen receptor α negative and Progesterone receptor positive breast cancer: lab error or real entity. Pathol Oncol Res 12(4):223–227

    Article  PubMed  Google Scholar 

  24. Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD et al (2004) Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36(4):417–422. doi:10.1038/ng1330

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

M. Wei is supported by Fund of Ministry of Education of China (No. 20050159020).

Author information

Authors and Affiliations

  1. Department of Pharmacology, China Medical University, Shenyang, Liaoning, 110001, People’s Republic of China

    Lin Zhao, Lin Wang, Jie Ren, Xiaoyan Wen, Miao He, Mingli Sun, Hongtao Tang & Minjie Wei

  2. Department of Physiology, Hrbin Medical University Daqing Branch, Daqing, Heilongjiang, 163319, People’s Republic of China

    Lin Wang

  3. Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People’s Republic of China

    Feng Jin

  4. Department of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People’s Republic of China

    Wenfeng Ma

Authors
  1. Lin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feng Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenfeng Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jie Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoyan Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Miao He
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mingli Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hongtao Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Minjie Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Minjie Wei.

Additional information

L. Zhao and L. Wang have contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zhao, L., Wang, L., Jin, F. et al. Silencing of estrogen receptor α (ERα) gene by promoter hypermethylation is a frequent event in Chinese women with sporadic breast cancer. Breast Cancer Res Treat 117, 253–259 (2009). https://doi.org/10.1007/s10549-008-0192-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-008-0192-1

Keywords

search

Navigation