Breast Cancer Research and Treatment

, Volume 128, Issue 2, pp 457–466 | Cite as

G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer

  • Atanas IgnatovEmail author
  • Tanja Ignatov
  • Christine Weißenborn
  • Holm Eggemann
  • Joachim Bischoff
  • Andrzej Semczuk
  • Albert Roessner
  • Serban Dan CostaEmail author
  • Thomas Kalinski
Clinical Trial


Recently, we have shown that the new G-protein-coupled estrogen receptor GPR30 plays an important role in the development of tamoxifen resistance in vitro. This study was undertaken to evaluate the correlation between GPR30 and tamoxifen resistance in breast cancer patients. GPR30 protein expression was evaluated by immunohistochemical analysis in 323 patients with primary operable breast cancer. The association between GPR30 expression and tamoxifen resistance was confirmed in a second cohort of 103 patients treated only with tamoxifen. Additionally, we evaluated GPR30 expression in 33 primary tumors and in recurrent tumors from the same patients. GPR30 expression was detected in 56.7% of the breast cancer specimens investigated and it correlated with overexpression of HER-2 (P = 0.021), EGFR (P = 0.024) and lymph node status (P = 0.047). In a first cohort, survival analysis showed that GPR30 was negatively correlated with relapse-free survival (RFS) only in patients treated with tamoxifen (tamoxifen with or without chemotherapy). GPR30 expression was associated with shorter RFS (HR = 1.768; 95% CI, 1.156–2.703; P = 0.009). In a subset of patients treated only with tamoxifen, multivariate analysis revealed that GPR30 expression is an independent unfavorable factor for RFS (HR = 4.440; 95% CI, 1.408–13.997; P = 0.011). In contrast, GPR30 tended to be a favorable factor regarding RFS in patients who did not receive tamoxifen. In 33 paired biopsies obtained before and after adjuvant therapy, GPR30 expression significantly increased only under tamoxifen treatment (P = 0.001). GPR30 expression in breast cancer independently predicts a poor RFS in patients treated with tamoxifen.


GPR30 Breast cancer Tamoxifen resistance Estrogen receptor 



We thank Carola Kügler und Claudia Miethke for excellent technical assistance. This work was supported by Deutsche Krebshilfe (Förderzeichen 108931).

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

10549_2011_1584_MOESM1_ESM.doc (22 kb)
Supplementary material 1 (DOC 22 kb)
10549_2011_1584_MOESM2_ESM.ppt (118 kb)
Supplementary material 2 (PPT 118 kb)


  1. 1.
    Early Breast Cancer Trialists’ Collaborative Group (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351:1451–1467CrossRefGoogle Scholar
  2. 2.
    Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M (2007) Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst 99:283–290PubMedCrossRefGoogle Scholar
  3. 3.
    Hutcheson IR, Knowlden JM, Madden TA, Barrow D, Gee JM, Wakeling AE, Nicholson RI (2003) Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells. Breast Cancer Res Treat 81:81–93PubMedCrossRefGoogle Scholar
  4. 4.
    Ignatov A, Ignatov T, Roessner A, Costa SD, Kalinski T (2009) Role of GPR30 in the mechanisms of tamoxifen resistance in breast cancer MCF-7 cells. Breast Cancer Res Treat 123:87–96PubMedCrossRefGoogle Scholar
  5. 5.
    Rae JM, Johnson MD (2005) What does an orphan G-protein-coupled receptor have to do with estrogen? Breast Cancer Res 7:243–244PubMedCrossRefGoogle Scholar
  6. 6.
    Prossnitz ER, Oprea TI, Sklar LA, Arterburn JB (2008) The ins and outs of GPR30: a transmembrane estrogen receptor. J Steroid Biochem Mol Biol 109:350–353PubMedCrossRefGoogle Scholar
  7. 7.
    Filardo EJ, Quinn JA, Bland KI, Frackelton AR Jr (2000) Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol 14:1649–1660PubMedCrossRefGoogle Scholar
  8. 8.
    Pandey DP, Lappano R, Albanito L, Madeo A, Maggiolini M, Picard D (2009) Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J 28:523–532PubMedCrossRefGoogle Scholar
  9. 9.
    Thomas P, Pang Y, Filardo EJ, Dong J (2005) Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 146:624–632PubMedCrossRefGoogle Scholar
  10. 10.
    Vivacqua A, Bonofiglio D, Recchia AG, Musti AM, Picard D, Ando S, Maggiolini M (2006) The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17beta-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol Endocrinol 20:631–646PubMedCrossRefGoogle Scholar
  11. 11.
    Vivacqua A, Bonofiglio D, Albanito L, Madeo A, Rago V, Carpino A, Musti AM, Picard D, Ando S, Maggiolini M (2006) 17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the g protein-coupled receptor GPR30. Mol Pharmacol 70:1414–1423PubMedCrossRefGoogle Scholar
  12. 12.
    Osborne CK, Shou J, Massarweh S, Schiff R (2005) Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 11:865s–870sPubMedGoogle Scholar
  13. 13.
    Ignatov T, Eggemann H, Semczuk A, Smith B, Bischoff J, Roessner A, Costa SD, Kalinski T, Ignatov A (2010) Role of GPR30 in endometrial pathology after tamoxifen for breast cancer. Am J Obstet Gynecol 203:595.e9–e16PubMedCrossRefGoogle Scholar
  14. 14.
    Filardo E, Quinn J, Pang Y, Graeber C, Shaw S, Dong J, Thomas P (2007) Activation of the novel estrogen receptor G protein-coupled receptor 30 (GPR30) at the plasma membrane. Endocrinology 148:3236–3245PubMedCrossRefGoogle Scholar
  15. 15.
    Kang L, Zhang X, Xie Y, Tu Y, Wang D, Liu Z, Wang ZY (2010) Involvement of estrogen receptor variant ER-alpha36, not GPR30, in nongenomic estrogen signaling. Mol Endocrinol 24:709–721PubMedCrossRefGoogle Scholar
  16. 16.
    Giltnane JM, Ryden L, Cregger M, Bendahl PO, Jirstrom K, Rimm DL (2007) Quantitative measurement of epidermal growth factor receptor is a negative predictive factor for tamoxifen response in hormone receptor positive premenopausal breast cancer. J Clin Oncol 25:3007–3014PubMedCrossRefGoogle Scholar
  17. 17.
    Hayward JL, Carbone PP, Heusen JC, Kumaoka S, Segaloff A, Rubens RD (1977) Assessment of response to therapy in advanced breast cancer. Br J Cancer 35:292–298PubMedCrossRefGoogle Scholar
  18. 18.
    Filardo EJ, Graeber CT, Quinn JA, Resnick MB, Giri D, DeLellis RA, Steinhoff MM, Sabo E (2006) Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin Cancer Res 12:6359–6366PubMedCrossRefGoogle Scholar
  19. 19.
    Liu Q, Li JG, Zheng XY, Jin F, Dong HT (2009) Expression of CD133, PAX2, ESA, and GPR30 in invasive ductal breast carcinomas. Chin Med J (Engl.) 122:2763–2769Google Scholar
  20. 20.
    Smith HO, Leslie KK, Singh M, Qualls CR, Revankar CM, Joste NE, Prossnitz ER (2007) GPR30: a novel indicator of poor survival for endometrial carcinoma. Am J Obstet Gynecol 196:386–389PubMedGoogle Scholar
  21. 21.
    Filardo EJ, Quinn JA, Sabo E (2008) Association of the membrane estrogen receptor, GPR30, with breast tumor metastasis and transactivation of the epidermal growth factor receptor. Steroids 73:870–873PubMedCrossRefGoogle Scholar
  22. 22.
    Albanito L, Sisci D, Aquila S, Brunelli E, Vivacqua A, Madeo A, Lappano R, Pandey DP, Picard D, Mauro L, Ando S, Maggiolini M (2008) Epidermal growth factor induces G protein-coupled receptor 30 expression in estrogen receptor-negative breast cancer cells. Endocrinology 149:3799–3808PubMedCrossRefGoogle Scholar
  23. 23.
    Vivacqua A, Lappano R, De Marco P, Sisci D, Aquila S, De Amicis F, Fuqua SA, Ando S, Maggiolini M (2009) G Protein-coupled receptor 30 expression is up-regulated by EGF and TGFα in estrogen receptor α-positive cancer cells. Mol Endocrinol 23:1815–1826PubMedCrossRefGoogle Scholar
  24. 24.
    King CR, Kraus MH, Aaronson SA (1985) Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 229:974–976PubMedCrossRefGoogle Scholar
  25. 25.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182PubMedCrossRefGoogle Scholar
  26. 26.
    van de Vijver MJ, Mooi WJ, Wisman P, Peterse JL, Nusse R (1988) Immunohistochemical detection of the neu protein in tissue sections of human breast tumors with amplified neu DNA. Oncogene 2:175–178PubMedGoogle Scholar
  27. 27.
    Borg A, Baldetorp B, Ferno M, Killander D, Olsson H, Ryden S, Sigurdsson H (1994) ERBB2 amplification is associated with tamoxifen resistance in steroid-receptor positive breast cancer. Cancer Lett 81:137–144PubMedCrossRefGoogle Scholar
  28. 28.
    Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M (2001) Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 19:3808–3816PubMedGoogle Scholar
  29. 29.
    Houston SJ, Plunkett TA, Barnes DM, Smith P, Rubens RD, Miles DW (1999) Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br J Cancer 79:1220–1226PubMedCrossRefGoogle Scholar
  30. 30.
    Knoop AS, Bentzen SM, Nielsen MM, Rasmussen BB, Rose C (2001) Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients. J Clin Oncol 19:3376–3384PubMedGoogle Scholar
  31. 31.
    Soubeyran I, Quenel N, Mauriac L, Durand M, Bonichon F, Coindre J-M (1996) Variation of hormonal receptor, pS2, c-erbB-2 and GSTpi contents in breast carcinomas under tamoxifen: a study of 74 cases. Br J Cancer 73:735–743PubMedCrossRefGoogle Scholar
  32. 32.
    Ariazi EA, Brailoiu E, Yerrum S, Shupp HA, Slifker MJ, Cunliffe HE, Black MA, Donato AL, Arterburn JB, Oprea TI, Prossnitz ER, Dun NJ, Jordan VC (2010) The G protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells. Cancer Res 70:1184–1194PubMedCrossRefGoogle Scholar
  33. 33.
    Kuo WH, Chang LY, Liu DL, Hwa HL, Lin JJ, Lee PH, Chen CN, Lien HC, Yuan RH, Shun CT, Chang KJ, Hsieh FJ (2007) The interactions between GPR30 and the major biomarkers in infiltrating ductal carcinoma of the breast in an Asian population. Taiwan J Obstet Gynecol 46:135–145PubMedCrossRefGoogle Scholar
  34. 34.
    Levin ER (2009) G protein-coupled receptor 30: estrogen receptor or collaborator? Endocrinology 150:1563–1565PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Atanas Ignatov
    • 1
    Email author
  • Tanja Ignatov
    • 1
  • Christine Weißenborn
    • 1
  • Holm Eggemann
    • 1
  • Joachim Bischoff
    • 1
  • Andrzej Semczuk
    • 2
  • Albert Roessner
    • 3
  • Serban Dan Costa
    • 1
    Email author
  • Thomas Kalinski
    • 3
  1. 1.Department of Obstetrics and GynecologyOtto-von-Guericke UniversityMagdeburgGermany
  2. 2.2nd Department of GynecologyLublin Medical UniversityLublinPoland
  3. 3.Department of PathologyOtto-von-Guericke UniversityMagdeburgGermany

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