Breast Cancer Research and Treatment

, Volume 100, Issue 2, pp 169–176 | Cite as

Association of GSTP1 CpG Islands Hypermethylation with Poor Prognosis in Human Breast Cancers

  • Takashi Arai
  • Yasuo Miyoshi
  • Seung Jin Kim
  • Tetsuya Taguchi
  • Yasuhiro Tamaki
  • Shinzaburo NoguchiEmail author
Clinical Trial


Glutathione S-transferase P1 (GSTP1) belongs to a family of phase II metabolic enzymes that can detoxify the carcinogens and cytotoxic drugs by conjugating them with glutathione. Relationship of GSTP1 CpG islands hypermethylation or GSTP1 protein expression with clinicopathological characteristics of breast cancers was studied. The CpG islands hypermethylation status of GSTP1 gene was studied by methylation specific primer assay and GSTP1 expression was studied by immunohistochemistry in primary breast cancers. Of 174 breast tumors, 24 (14%) were found to have GSTP1 CpG islands hypermethylation. A significant association was found between GSTP1 CpG islands hypermethylation and large tumor size (P < 0.01) or lymph node metastases (P < 0.05). Relapse-free survival (RFS) rates of patients with GSTP1 CpG islands hypermethylation were significantly poorer than those without it (5-year RFS rates; 60 vs. 86%, P < 0.01). Multivariate analysis showed that GSTP1 CpG islands hypermethylation status was a statistically significant prognostic factor being independent of other conventional prognostic factors. Immunohistochemical study showed that here was a significant association between GSTP1 CpG islands hypermethylation and loss of GSTP1 expression (P < 0.01) but that RFS rates of patients with GSTP1 positive tumors were not significantly different from those with GSTP1 negative tumors. GSTP1 CpG islands hypermethylation, but not GSTP1 protein expression, is associated with a poor prognosis of breast cancers, suggesting that GSTP1 CpG islands hypermethylation has a potential to serve as a clinically useful prognostic factor.

Key words

GSTP1 Hypermethylation Breast cancer Prognosis 



Lymph node


Estrogen receptor


Progesterone receptor


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  1. 1.
    Coles BF, Kadlubar FF (2003) Detoxification of electrophilic compounds by glutathione S-transferase catalysis: determinants of individual response to chemical carcinogens and chemotherapeutic drugs? Biofactors 17:115–130PubMedGoogle Scholar
  2. 2.
    Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, Kensler TW (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 98:3410–3415PubMedCrossRefGoogle Scholar
  3. 3.
    Cairns J, Wright C, Cattan AR, Hall AG, Cantwell BJ, Harris AL, Horne CH (1992) Immunohistochemical demonstration of glutathione S-transferases in primary human breast carcinomas. J Pathol 166:19–25PubMedCrossRefGoogle Scholar
  4. 4.
    Nakayama M, Gonzalgo ML, Yegnasubramanian S, Lin X, De Marzo AM, Nelson WG (2004) GSTP1 CpG island hypermethylation as a molecular biomarker for prostate cancer. J Cell Biochem 91:540–552PubMedCrossRefGoogle Scholar
  5. 5.
    Henderson CJ, Smith AG, Ure J, Brown K, Bacon EJ, Wolf CR (1998) Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases. Proc Natl Acad Sci USA 95:5275–5280PubMedCrossRefGoogle Scholar
  6. 6.
    Brotherick I, Shenton BK, Egan M, Cunliffe WE, Browell DA, Lunt LG, Young JR, Higgs MJ (1996) Examination of multidrug resistance in cell lines and primary breast tumours by flow cytometry. Eur J Cancer 32A: 2334–2341PubMedCrossRefGoogle Scholar
  7. 7.
    Wang T, Arifoglu P, Ronai Z, Tew KD (2001) Glutathione S-transferase P1-1 (GSTP1-1) inhibits c-Jun N-terminal kinase (JNK1) signaling through interaction with the C terminus. J Biol Chem 276:20999–21003PubMedCrossRefGoogle Scholar
  8. 8.
    Gilbert L, Elwood LJ, Merino M, Masood S, Barnes R, Steinberg SM, Lazarous DF, Pierce L, d’Angelo T, Moscow JA et al (1993) A pilot study of pi-class glutathione S-transferase expression in breast cancer: correlation with estrogen receptor expression and prognosis in node-negative breast cancer. J Clin Oncol 11:49–58PubMedGoogle Scholar
  9. 9.
    Silvestrini R, Veneroni S, Benini E, Daidone MG, Luisi A, Leutner M, Maucione A, Kenda R, Zucali R, Veronesi U (1997) Expression of p53, glutathione S-transferase-pi, and Bcl-2 proteins and benefit from adjuvant radiotherapy in breast cancer. J Natl Cancer Inst 89:639–645PubMedCrossRefGoogle Scholar
  10. 10.
    Huang J, Tan PH, Thiyagarajan J, Bay BH (2003) Prognostic significance of glutathione S-transferase-pi in invasive breast cancer. Mod Pathol 16:558–565PubMedCrossRefGoogle Scholar
  11. 11.
    Su F, Hu X, Jia W, Gong C, Song E, Hamar P (2003) Glutathion S transferase pi indicates chemotherapy resistance in breast cancer. J Surg Res 113:102–108PubMedCrossRefGoogle Scholar
  12. 12.
    Parrella P, Poeta ML, Gallo AP, Prencipe M, Scintu M, Apicella A, Rossiello R, Liguoro G, Seripa D, Gravina C, Rabitti C, Rinaldi M, Nicol T, Tommasi S, Paradiso A, Schittulli F, Altomare V, Fazio VM (2004) Nonrandom distribution of aberrant promoter methylation of cancer-related genes in sporadic breast tumors. Clin Cancer Res 10:5349–5354PubMedCrossRefGoogle Scholar
  13. 13.
    Shinozaki M, Hoon DS, Giuliano AE, Hansen NM, Wang HJ, Turner R, Taback B (2005) Distinct hypermethylation profile of primary breast cancer is associated with sentinel lymph node metastasis. Clin Cancer Res 11:2156–2162PubMedCrossRefGoogle Scholar
  14. 14.
    Esteller M, Corn PG, Urena JM, Gabrielson E, Baylin SB, Herman JG (1998) Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. Cancer Res 58:4515–4518PubMedGoogle Scholar
  15. 15.
    Goldhirsch A, Wood WC, Senn HJ, Glick JH, Gelber RD (1995) Fifth international conference on adjuvant therapy of breast cancer, St Gallen, March 1995. International consensus panel on the treatment of primary breast cancer. Eur J Cancer 31A:1754–1759PubMedCrossRefGoogle Scholar
  16. 16.
    Adjuvant Therapy of Primary Breast Cancer (1998) 6th international conference. Olma Messen, St. Gallen, February 25–28, 1998. Abstracts. Eur J Cancer 34 (Suppl 1):S3–S45Google Scholar
  17. 17.
    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 93:9821–9826PubMedCrossRefGoogle Scholar
  18. 18.
    Jeronimo C, Costa I, Martins MC, Monteiro P, Lisboa S, Palmeira C, Henrique R, Teixeira MR, Lopes C (2003) Detection of gene promoter hypermethylation in fine needle washings from breast lesions. Clin Cancer Res 9:3413–3417PubMedGoogle Scholar
  19. 19.
    Krassenstein R, Sauter E, Dulaimi E, Battagli C, Ehya H, Klein-Szanto A, Cairns P (2004) Detection of breast cancer in nipple aspirate fluid by CpG island hypermethylation. Clin Cancer Res 10:28–32PubMedCrossRefGoogle Scholar
  20. 20.
    Bernardini S, Miano R, Iori R, Finazzi-Agro E, Palmieri G, Ballerini S, Angeloni C, Orlandi A, Bellincampi L, Cortese C, Federici G (2004) Hypermethylation of the CpG islands in the promoter region of the GSTP1 gene in prostate cancer: a useful diagnostic and prognostic marker?. Clin Chim Acta 350:181–188PubMedCrossRefGoogle Scholar
  21. 21.
    Chan QK, Khoo US, Chan KY, Ngan HY, Li SS, Chiu PM, Man LS, Ip PP, Xue WC, Cheung AN (2005) Promoter methylation and differential expression of pi-class glutathione S-transferase in endometrial carcinoma. J Mol Diagn 7:8–16PubMedGoogle Scholar
  22. 22.
    Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH (2003) Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 163:1371–1378PubMedGoogle Scholar
  23. 23.
    Bellamy CO, Harrison DJ (1994) Evaluation of glutathione S-transferase Pi in non-invasive ductal carcinoma of breast. Br J Cancer 69:183–185PubMedGoogle Scholar
  24. 24.
    Peters WH, Roelofs HM, van Putten WL, Jansen JB, Klijn JG, Foekens JA (1993) Response to adjuvant chemotherapy in primary breast cancer: no correlation with expression of glutathione S-transferases. Br J Cancer 68:86–92PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • Takashi Arai
    • 1
  • Yasuo Miyoshi
    • 1
  • Seung Jin Kim
    • 1
  • Tetsuya Taguchi
    • 1
  • Yasuhiro Tamaki
    • 1
  • Shinzaburo Noguchi
    • 1
    Email author
  1. 1.Department of Surgical OncologyOsaka University Graduate School of MedicineOsakaJapan

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