Skip to main content

Advertisement

SpringerLink
Log in

Estrogen receptor-alpha promoter methylation in sporadic basal-like breast cancer of Chinese women

  • Research Article
  • Published:
Tumor Biology

Abstract

Basal-like breast cancer (BLBC) appears to be characterized by a relatively unfavorable prognosis and lack of a specific therapeutic target. Estrogen receptor-alpha (ERα) has been widely accepted as a prognostic marker and a predictor for endocrine therapy response of breast cancer. This study aimed to clarify the correlation of ERα methylation with the pathogenesis and clinicopathological significance of sporadic BLBC of Chinese women without a family history of the cancer. The methylation of ERα promoter was investigated in genomic DNA of 60 sporadic BLBC with 108 cases of non-BLBC as control by methylation-specific polymerase chain reaction. We also investigated the expression of p53, breast cancer gene (BRCA)-1, and BRCA-2 by immunohistochemistry and analyzed the correlation between ERα methylation and clinicopathological features of BLBC. ERα methylation was observed in 48 of 60 (80.0%) sporadic BLBC, which was significantly higher than in sporadic non-BLBC cancer (47/108, 43.5%; χ2 = 20.89, p < 0.01). No correlation was found between the ERα methylation and age and menopausal status, while it was significantly associated with lymph node metastasis, tumor stage, nuclear p53 accumulation, and BRCA-1 and BRCA-2 expression in sporadic BLBC. The ERα methylation status in basal-like breast cancer was significantly higher than in sporadic non-basal-like breast cancer. It was associated with the lymph node metastasis, tumor stage, p53 nuclear accumulation, and BRCA-1 and BRCA-2 expression in BLBC. It may play an important role in BLBC pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Liu Y, Ji R, Li J, Gu Q, Zhao X, Sun T, et al. Correlation effect of EGFR and CXCR4 and CCR7 chemokine receptors in predicting breast cancer metastasis and prognosis. J Exp Clin Cancer Res. 2010;29:16.

    Article  PubMed  Google Scholar 

  2. Zhuo W, Zhang Y, Xiang Z, Cai L, Chen Z. Polymorphisms of TP53 codon 72 with breast carcinoma risk: evidence from 12226 cases and 10782 controls. J Exp Clin Cancer Res. 2009;28:115.

    Article  PubMed  Google Scholar 

  3. Kurose K, Hoshaw-Woodard S, Adeyinka A, Lemeshow S, Watson PH, Eng C. Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour–microenvironment interactions. Hum Mol Genet. 2001;10:1907–12.

    Article  PubMed  CAS  Google Scholar 

  4. Mao XY, Fan CF, Zheng HC, Wei J, Yao F, Jin F. p53 nuclear accumulation and ERalpha expression in ductal hyperplasia of breast in a cohort of 215 Chinese women. J Exp Clin Cancer Res. 2010;16:112.

    Article  Google Scholar 

  5. Jönsson G, Staaf J, Vallon-Christersson J, Ringnér M, Holm K, Hegardt C, et al. Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics. Breast Cancer Res. 2010;12:R42.

    Article  PubMed  Google Scholar 

  6. Ibrahim E, Al-Gahmi AM, Zeenelin AA, Zekri JM, Elkhodary TR, Gaballa HE, et al. Basal vs. luminal A breast cancer subtypes: a matched case–control study using estrogen receptor, progesterone receptor, and HER-2 as surrogate markers. Med Oncol. 2009;26:372–8.

    Article  PubMed  CAS  Google Scholar 

  7. Ihemelandu CU, Leffall Jr LD, Dewitty RL, Naab TJ, Mezghebe HM, Makambi KH, et al. Molecular breast cancer subtypes in premenopausal African-American women, tumor biologic factors and clinical outcome. Ann Surg Oncol. 2007;14:2994–3003.

    Article  PubMed  Google Scholar 

  8. Onitilo AA, Engel JM, Greenlee RT, Mukesh BN. Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res. 2009;7:4–13.

    Article  PubMed  CAS  Google Scholar 

  9. Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A, et al. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell. 2006;9:121–32.

    Article  PubMed  CAS  Google Scholar 

  10. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10:5367–74.

    Article  PubMed  CAS  Google Scholar 

  11. Yu W, Kanaan Y, Bae YK, Gabrielson E. Chromosomal changes in aggressive breast cancers with basal-like features. Cancer Genet Cytogenet. 2009;193:29–37.

    Article  PubMed  CAS  Google Scholar 

  12. Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res. 2008;14:1368–76.

    Article  PubMed  CAS  Google Scholar 

  13. Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol. 2006;19:264–71.

    Article  PubMed  CAS  Google Scholar 

  14. Kok LF, Lee MY, Tyan YS, Wu TS, Cheng YW, Kung MF, et al. Comparing the scoring mechanisms of p16INK4a immunohistochemistry based on independent nucleic stains and independent cytoplasmic stains in distinguishing between endocervical and endometrial adenocarcinomas in a tissue microarray study. Arch Gynecol Obstet. 2010;281:293–300.

    Article  PubMed  CAS  Google Scholar 

  15. Koo CL, Kok LF, Lee MY, Wu TS, Cheng YW, Hsu JD, et al. Scoring mechanisms of p16INK4a immunohistochemistry based on either independent nucleic stain or mixed cytoplasmic with nucleic expression can significantly signal to distinguish between endocervical and endometrial adenocarcinomas in a tissue microarray study. J Transl Med. 2009;7:25.

    Article  PubMed  Google Scholar 

  16. Manne U, Myers RB, Moron C, Poczatek RB, Dillard S, Weiss H, et al. Prognostic significance of Bcl-2 expression and p53 nuclear accumulation in colorectal adenocarcinoma. Int J Cancer. 1997;74:346–58.

    Article  PubMed  CAS  Google Scholar 

  17. Hatanaka Y, Hashizume K, Kamihara Y, Itoh H, Tsuda H, Osamura RY, et al. Quantitative immunohistochemical evaluation of HER2/neu expression with HercepTestTM in breast carcinoma by image analysis. Pathol Int. 2001;51:33–6.

    Article  PubMed  CAS  Google Scholar 

  18. Hoff ER, Tubbs RR, Myles JL, Procop GW. HER2/neu amplification in breast cancer: stratification by tumor type and grade. Am J Clin Pathol. 2002;117:916–21.

    Article  PubMed  CAS  Google Scholar 

  19. Yang XR, Sherman ME, Rimm DL, Lissowska J, Brinton LA, Peplonska B, et al. Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomark Prev. 2007;16:439–43.

    Article  CAS  Google Scholar 

  20. Lapidus RG, Nass SJ, Butash KA, Parl FF, Weitzman SA, Graff JG, et al. Mapping of ER gene CpG island methylation-specific polymerase chain reaction. Cancer Res. 1998;58:2515–9.

    PubMed  CAS  Google Scholar 

  21. Travis RC, Key TJ. Oestrogen exposure and breast cancer risk. Breast Cancer Res. 2003;5:239–47.

    Article  PubMed  CAS  Google Scholar 

  22. Willems P, De Ruyck K, Van den Broecke R, Makar A, Perletti G, Thierens H, et al. Polymorphism in the promoter region of Ku70/XRCC6, associated with breast cancer risk and oestrogen exposure. J Cancer Res Clin Oncol. 2009;135:1159–68.

    Article  PubMed  CAS  Google Scholar 

  23. Cheng AS, Culhane AC, Chan MW, Venkataramu CR, Ehrich M, Nasir A, et al. Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome. Cancer Res. 2008;68:1786–96.

    Article  PubMed  CAS  Google Scholar 

  24. Duss S, André S, Nicoulaz AL, Fiche M, Bonnefoi H, Brisken C, et al. An oestrogen-dependent model of breast cancer created by transformation of normal human mammary epithelial cells. Breast Cancer Res. 2007;9:R38.

    Article  PubMed  Google Scholar 

  25. Polyak K. Breast cancer: origins and evolution. J Clin Invest. 2007;117:3155–63.

    Article  PubMed  CAS  Google Scholar 

  26. Matthews J, Gustafsson JA. Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol Interv. 2003;3:281–92.

    Article  PubMed  CAS  Google Scholar 

  27. Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res. 2007;9:R6.

    Article  PubMed  Google Scholar 

  28. Goldhirsch A, Gelber RD, Coates AS. What are the long-term effects of chemotherapy and hormonal therapy for early breast cancer? Nat Clin Pract Oncol. 2005;2:440–1.

    Article  PubMed  Google Scholar 

  29. Yang X, Phillips DL, Ferguson AT, Nelson WG, Herman JG, Davidson NE. Synergistic activation of functional estrogen receptor (ER)-alpha by DNA methyltransferase and histone deacetylase inhibition in human ER-alpha-negative breast cancer cells. Cancer Res. 2001;61:7025–9.

    PubMed  CAS  Google Scholar 

  30. Bohn OL, Fuertes-Camilo M, Navarro L, Saldivar J, Sanchez-Sosa S. p16INK4a expression in basal-like breast carcinoma. Int J Clin Exp Pathol. 2010;3:600–7.

    PubMed  Google Scholar 

  31. Herschkowitz JI, He X, Fan C, Perou CM. The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res. 2008;10:R75.

    Article  PubMed  Google Scholar 

  32. Haupt B, Ro JY, Schwartz MR. Basal-like breast carcinoma: a phenotypically distinct entity. Arch Pathol Lab Med. 2010;134:130–3.

    PubMed  Google Scholar 

  33. Asada H, Yamagata Y, Taketani T, Matsuoka A, Tamura H, Hattori N, et al. Potential link between estrogen receptor-alpha gene hypomethylation and uterine fibroid formation. Mol Hum Reprod. 2008;14:539–45.

    Article  PubMed  CAS  Google Scholar 

  34. Huang YS, Zhi YF, Wang SR. Hypermethylation of estrogen receptor-alpha gene in atheromatosis patients and its correlation with homocysteine. Pathophysiology. 2009;16:259–65.

    Article  PubMed  CAS  Google Scholar 

  35. Berger J, Daxenbichler G. DNA methylation of nuclear receptor genes—possible role in malignancy. J Steroid Biochem Mol Biol. 2002;80:1–11.

    Article  PubMed  CAS  Google Scholar 

  36. Yoshida T, Eguchi H, Nakachi K, Tanimoto K, Higashi Y, Suemasu K, et al. Distinct mechanisms of loss of estrogen receptor alpha gene expression in human breast cancer: methylation of the gene and alteration of trans-acting factors. Carcinogenesis. 2000;21:2193–201.

    Article  PubMed  CAS  Google Scholar 

  37. Zhao L, Wang L, Jin F, Ma W, Ren J, Wen X, et al. Silencing of estrogen receptor alpha (ERalpha) gene by promoter hypermethylation is a frequent event in Chinese women with sporadic breast cancer. Breast Cancer Res Treat. 2009;117:253–9.

    Article  PubMed  CAS  Google Scholar 

  38. Harder J, Engelstaedter V, Usadel H, Lassmann S, Werner M, Baier P, et al. CpG-island methylation of the ER promoter in colorectal cancer: analysis of micrometastases in lymph nodes from UICC stage I and II patients. Br J Cancer. 2009;100:360–5.

    Article  PubMed  CAS  Google Scholar 

  39. Dookeran KA, Dignam JJ, Ferrer K, Sekosan M, McCaskill-Stevens W, Gehlert S. p53 as a marker of prognosis in African-American women with breast cancer. Ann Surg Oncol. 2010;17:1398–405.

    Article  PubMed  Google Scholar 

  40. Kim MJ, Ro JY, Ahn SH, Kim HH, Kim SB, Gong G. Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and Her2/neu-overexpressing phenotypes. Hum Pathol. 2006;37:1217–26.

    Article  PubMed  CAS  Google Scholar 

  41. Livasy CA, Perou CM, Karaca G, Cowan DW, Maia D, Jackson S, et al. Identification of a basal-like subtype of breast ductal carcinoma in situ. Hum Pathol. 2007;38:197–204.

    Article  PubMed  CAS  Google Scholar 

  42. Rakha EA, Putti TC, Abd El-Rehim DM, Paish C, Green AR, Powe DG, et al. Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation. J Pathol. 2006;208:495–506.

    Article  PubMed  CAS  Google Scholar 

  43. Li S, Rong M, Iacopetta B. DNA hypermethylation in breast cancer and its association with clinicopathological features. Cancer Lett. 2006;237:272–80.

    Article  PubMed  CAS  Google Scholar 

  44. Sayeed A, Konduri SD, Liu W, Bansal S, Li F, Das GM. Estrogen receptor alpha inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis. Cancer Res. 2007;67:7746–55.

    Article  PubMed  CAS  Google Scholar 

  45. James CR, Quinn JE, Mullan PB, Johnston PG, Harkin DP. BRCA1, a potential predictive biomarker in the treatment of breast cancer. Oncologist. 2007;12:142–50.

    Google Scholar 

  46. Melchor L, Benítez J. An integrative hypothesis about the origin and development of sporadic and familial breast cancer subtypes. Carcinogenesis. 2008;29:1475–82.

    Article  PubMed  CAS  Google Scholar 

  47. Sørlie, Wang Y, Xiao C, Johnsen H, Naume B, Samaha RR, et al. Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms. BMC Genomics. 2006;7:127.

    Article  PubMed  Google Scholar 

  48. Foulkes WD, Brunet JS, Stefansson IM, Straume O, Chappuis PO, Bégin LR, et al. The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res. 2004;64:830–5.

    Article  PubMed  CAS  Google Scholar 

  49. Jeffy BD, Hockings JK, Kemp MQ, Morgan SS, Hager JA, Beliakoff J, et al. An estrogen receptor-alpha/p300 complex activates the BRCA-1 promoter at an AP-1 site that binds Jun/Fos transcription factors: repressive effects of p53 on BRCA-1 transcription. Neoplasia. 2005;7:873–82.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This work was supported by the National Natural Science Foundation of China (No. 30950009).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Breast Surgery, Department of Surgical Oncology, Research Unit of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001, Liaoning Province, People’s Republic of China

    Ming-xi Jing, Xiao-yun Mao, Chao Li, Jing Wei, Chong Liu & Feng Jin

Authors
  1. Ming-xi Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-yun Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Feng Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Feng Jin.

Additional information

Ming-xi Jing and Xiao-yun Mao contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jing, Mx., Mao, Xy., Li, C. et al. Estrogen receptor-alpha promoter methylation in sporadic basal-like breast cancer of Chinese women. Tumor Biol. 32, 713–719 (2011). https://doi.org/10.1007/s13277-011-0172-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-011-0172-7

Keywords

Search

Navigation