Breast Cancer Research and Treatment

, Volume 123, Issue 1, pp 51–58 | Cite as

GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer

  • Hugo Arias-Pulido
  • Melanie Royce
  • Yun Gong
  • Nancy Joste
  • Lesley Lomo
  • Sang-Joon Lee
  • Nabila Chaher
  • Claire Verschraegen
  • Juanita Lara
  • Eric R. Prossnitz
  • Massimo Cristofanilli
Preclinical Study


GPR30 is a novel G protein-coupled estrogen receptor (ER) associated with metastases in breast cancer (BC) and poor survival in endometrial and ovarian tumors. The association of GPR30 expression with inflammatory breast cancer (IBC), an aggressive and commonly hormone-independent form of BC, has not been studied. GPR30, ER, progesterone receptor (PR), epidermal growth factor receptor (EGFR), and HER-2 expression were assessed by immunohistochemistry (and FISH for HER-2) in 88 primary IBCs. GPR30 expression was correlated with patient overall survival (OS), disease-free survival (DFS), pathologic variables, and other biomarkers. GPR30 expression was found in 69% of IBC cases. ER, PR, HER-2, and EGFR were found in 43, 35, 39, and 34% of IBC cases, respectively. GPR30 expression correlated inversely with ER expression (P = 0.02). Co-expression of ER and GPR30 was found in 24% of IBC samples; 19% expressed only ER and 46% expressed only GPR30. Univariate analysis showed no association between GPR30 expression and OS or DFS. However, co-expression of ER and GPR30 was associated with improved OS (P < 0.03) and marginally with DFS (P < 0.06); the absence of both ER and GPR30 was associated with worse OS and DFS (P = 0.03 for both). Multivariate analysis identified ER as an independent prognostic factor of OS (P = 0.008) and DFS (P = 0.02). The majority of IBC tumors are GPR30-positive, suggesting that estrogen signaling may be active in ER-negative IBC patients. These findings suggest potential new therapeutic targets for IBC such as novel endocrine agents or direct modulation of GPR30.


Inflammatory breast cancer GPR30 Hormone receptors Growth factor receptors Overall survival Disease-free survival 

Supplementary material

10549_2009_631_MOESM2_ESM.pdf (20 kb)
Suppl. Fig. 1. Kaplan–Meier survival curves of OS (a) and DFS (b) time according to GPR30/ER patterns. (PDF 20 kb)
10549_2009_631_MOESM3_ESM.pdf (18 kb)
Suppl. Fig. 2. Kaplan–Meier survival curves of OS (a) and (b) time according to GPR30/ER status. (PDF 17 kb)
10549_2009_631_MOESM4_ESM.pdf (18 kb)
Suppl. Fig. 3. Kaplan–Meier survival curves of OS (a) and DFS (b) time according to ER status. (PDF 17 kb)


  1. 1.
    Levine PH, Veneroso C (2008) The epidemiology of inflammatory breast cancer. Semin Oncol 35:11–16CrossRefPubMedGoogle Scholar
  2. 2.
    Singletary SE, Cristofanilli M (2008) Defining the clinical diagnosis of inflammatory breast cancer. Semin Oncol 35:7–10CrossRefPubMedGoogle Scholar
  3. 3.
    Kerlikowske K, Miglioretti DL, Buist DSM, Walker R, Carney PA (2007) Declines in invasive breast cancer and use of postmenopausal hormone therapy in a screening mammography population. J Natl Cancer Inst 99:1335–1339CrossRefPubMedGoogle Scholar
  4. 4.
    Hance KW, Anderson WF, Devesa SS, Young HA, Levine PH (2005) Trends in inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program at the National Cancer Institute. J Natl Cancer Inst 97:966–975CrossRefPubMedGoogle Scholar
  5. 5.
    Molckovsky A, Fitzgerald B, Freedman O, Heisey R, Clemons M (2009) Approach to inflammatory breast cancer. Can Fam Physician 55:25–31PubMedGoogle Scholar
  6. 6.
    Panades M, Olivotto IA, Speers CH, Shenkier T, Olivotto TA, Weir L, Allan SJ, Truong PT (2005) Evolving treatment strategies for inflammatory breast cancer: a population-based survival analysis. J Clin Oncol 23:1941–1950CrossRefPubMedGoogle Scholar
  7. 7.
    Dawood S, Ueno N, Cristofanilli M (2008) The medical treatment of inflammatory breast cancer. Semin Oncol 35:64–71CrossRefPubMedGoogle Scholar
  8. 8.
    Charafe-Jauffret E, Tarpin C, Viens P, Bertucci F (2008) Defining the molecular biology of inflammatory breast cancer. Semin Oncol 35:41–50CrossRefPubMedGoogle Scholar
  9. 9.
    Gong Y (2008) Pathologic aspects of inflammatory breast cancer: Part 2. Biologic insights into its aggressive phenotype. Semin Oncol 35:33–40CrossRefPubMedGoogle Scholar
  10. 10.
    Ventura AC, Merajver SD (2008) Genetic determinants of aggressive breast cancer. Annu Rev Med 59:199–212CrossRefPubMedGoogle Scholar
  11. 11.
    Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307:1625–1630CrossRefPubMedGoogle Scholar
  12. 12.
    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 146:624–632CrossRefPubMedGoogle Scholar
  13. 13.
    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 14:1649–1660CrossRefPubMedGoogle Scholar
  14. 14.
    Kanda N, Watanabe S (2003) 17beta-estradiol inhibits oxidative stress-induced apoptosis in keratinocytes by promoting Bcl-2 expression. J Invest Dermatol 121:1500–1509CrossRefPubMedGoogle Scholar
  15. 15.
    Kanda N, Watanabe S (2004) 17beta-estradiol stimulates the growth of human keratinocytes by inducing cyclin D2 expression. J Invest Dermatol 123:319–328CrossRefPubMedGoogle Scholar
  16. 16.
    Prossnitz ER, Arterburn JB, Smith HO, Oprea TI, Sklar LA, Hathaway HJ (2008) Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annu Rev Physiol 70:165–190CrossRefPubMedGoogle Scholar
  17. 17.
    Filardo EJ, Quinn JA, Frackelton AR Jr, Bland KI (2002) Estrogen action via the g protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Mol Endocrinol 16:70–84CrossRefPubMedGoogle Scholar
  18. 18.
    Prossnitz ER, Sklar LA, Oprea TI, Arterburn JB (2008) GPR30: a novel therapeutic target in estrogen-related disease. Trends Pharmacol Sci 29:116–123PubMedGoogle Scholar
  19. 19.
    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 12:6359–6366CrossRefPubMedGoogle Scholar
  20. 20.
    Smith HA, Leslie K, Singh M, Qualls CR, Revankar CM, Joste N, Prossnitz ER (2007) GPR-30: a novel indicator of poor survival in endometrial carcinoma. Am J Obstet Gynecol 196:386.e381–386.e389Google Scholar
  21. 21.
    Smith H, Arias-Pulido H, Kuo D, Howard T, Qualls C, Lee S-J, Verschraegen C, Hathaway H, Joste N, Prossnitz E (2009) GPR30 predicts poor survival for ovarian cancer. Gynecol Oncol 114:465–471CrossRefPubMedGoogle Scholar
  22. 22.
    Ginestier C, Charafe-Jauffret E, Bertucci F, Eisinger F, Geneix J, Bechlian D, Conte N, Adelaide J, Toiron Y, Nguyen C et al (2002) Distinct and complementary information provided by use of tissue and DNA microarrays in the study of breast tumor markers. Am J Pathol 161:1223–1233PubMedGoogle Scholar
  23. 23.
    Cristofanilli M, Buzdar AU, Hortobagyi GN (2003) Update on the management of inflammatory breast cancer. Oncologist 8:141–148CrossRefPubMedGoogle Scholar
  24. 24.
    Cabioglu N, Gong Y, Islam R, Broglio KR, Sneige N, Sahin A, Gonzalez-Angulo AM, Morandi P, Bucana C, Hortobagyi GN et al (2007) Expression of growth factor and chemokine receptors: new insights in the biology of inflammatory breast cancer. Ann Oncol 18:1021–1029CrossRefPubMedGoogle Scholar
  25. 25.
    Gong Y, Booser D, Sneige N (2005) Comparison of HER-2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma. Cancer 103:1763–1769CrossRefPubMedGoogle Scholar
  26. 26.
    Lachin J (2000) Biostatistical methods. Wiley, New York, pp 272–285CrossRefGoogle Scholar
  27. 27.
    EBCTCG (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717CrossRefGoogle Scholar
  28. 28.
    Filardo EJ, Thomas P (2005) GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release. Trends Endocrinol Metab 16:362–367CrossRefPubMedGoogle Scholar
  29. 29.
    Kuo W, Chang L, Liu D, Hwa H, Lin J, Lee P, Chen C, Lien H, Yuan R, Shun C et al (2007) The interactions between GPR30 and the major biomarkers in infiltrating ductal carcinoma of the breast in an Asian population. Taiwan J Obstet Gynecol 46:135–145CrossRefPubMedGoogle Scholar
  30. 30.
    Hui A-M, Zhang W, Chen W, Xi D, Purow B, Friedman GC, Fine HA (2004) Agents with selective estrogen receptor (ER) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells. Cancer Res 64:9115–9123CrossRefPubMedGoogle Scholar
  31. 31.
    Teng J, Wang Z-Y, Prossnitz ER, Bjorling DE (2008) The G protein-coupled receptor GPR30 inhibits human urothelial cell proliferation. Endocrinology 149:4024–4034CrossRefPubMedGoogle Scholar
  32. 32.
    Bologa CG, Revankar CM, Young SM, Edwards BS, Arterburn JB, Kiselyov AS, Parker MA, Tkachenko SE, Savchuck NP, Sklar LA et al (2006) Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol 2:207–212CrossRefPubMedGoogle Scholar
  33. 33.
    Dennis M, Burai R, Ramesh C, Petrie W, Alcon S, Nayak T, Bologa C, Leitao A, Brailoiu E, Deliu E et al (2009) In vivo effects of a GPR30 antagonist. Nat Chem Biol 5:421–427CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Hugo Arias-Pulido
    • 1
  • Melanie Royce
    • 2
  • Yun Gong
    • 6
  • Nancy Joste
    • 3
  • Lesley Lomo
    • 3
  • Sang-Joon Lee
    • 4
  • Nabila Chaher
    • 7
  • Claire Verschraegen
    • 2
  • Juanita Lara
    • 6
  • Eric R. Prossnitz
    • 5
  • Massimo Cristofanilli
    • 6
  1. 1.Translational Therapeutics LaboratoryThe University of New Mexico Cancer CenterAlbuquerqueUSA
  2. 2.Division of Hematology/OncologyThe University of New Mexico Cancer CenterAlbuquerqueUSA
  3. 3.Department of PathologyThe University of New Mexico Cancer CenterAlbuquerqueUSA
  4. 4.Division of Epidemiology and BiostatisticsThe University of New Mexico Cancer CenterAlbuquerqueUSA
  5. 5.Cell Biology and PhysiologyThe University of New Mexico Cancer CenterAlbuquerqueUSA
  6. 6.Department of Pathology, and Breast Medical Oncology – The Morgan Welch Inflammatory Breast Cancer Research Program and ClinicThe University of Texas MD Anderson Cancer CenterHoustonUSA
  7. 7.Department of PathologyCentre Pierre et Marie CurieAlgiersAlgeria

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