Top

Published in:

01-02-2019 | Preclinical study

G-protein-coupled estrogen receptor GPER-1 expression in hormone receptor-positive breast cancer is associated with poor benefit of tamoxifen

Authors: Tanja Ignatov, Maria Claus, Norbert Nass, Johannes Haybaeck, Bernd Seifert, Thomas Kalinski, Olaf Ortmann, Atanas Ignatov

Published in: Breast Cancer Research and Treatment | Issue 1/2019

Abstract

Background

The role of G-protein-coupled estrogen receptor 1 (GPER-1) in the development of tamoxifen resistance in breast cancer is a highly controversial issue. The aim of this study was to determine the expression of GPER-1 in the clinical routine under conditions of endocrine treatment.

Patients and methods

GPER-1 expression was analyzed in 442 patients with primary invasive breast cancer. GPER-1 score of > 3 was determined as positive. Expression data were correlated with clinical and pathological characteristics and patient survival.

Results

GPER-1 expression was observed in 352 (80.9%) cases, and positively correlated with estrogen and progesterone receptor status (p = 0.0001). GPER-1 positivity was associated with an increased grade of differentiation (p = 0.0001) and with a low level of Ki-67 expression (p = 0.0001). High GPER-1 expression was associated with a decreased level upon systemic treatment (p = 0.011). In the whole cohort, GPER-1 expression was associated with prolonged disease-free survival (DFS). DFS between tamoxifen- and aromatase inhibitor-treated GPER-1-positive patients was similar (p = 0.090). Notably, after matching the analysis for the most important prognostic factors, DFS for tamoxifen-treated GPER-1-positive patients was 69.1%, which is a percentage that is significantly lower compared to DFS for GPER-1-positive patients treated with aromatase inhibitors (92.7%) (p = 0.005).

Conclusion

GPER-1 expression is a favorable prognostic factor in breast cancer patients. Its predictive role for poor benefit form tamoxifen treatment should be investigated in further studies.

Molina L, Figueroa CD, Bhoola KD, Ehrenfeld P (2017) GPER-1/GPR30 a novel estrogen receptor sited in the cell membrane: therapeutic coupling to breast cancer. Expert Opin Ther Targets 21:755–766CrossRefPubMed

Ignatov A, Ignatov T, Weissenborn C et al (2011) G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer. Breast Cancer Res Treat 128:457–466CrossRefPubMed

Sjostrom M, Hartman L, Grabau D et al (2014) Lack of G protein-coupled estrogen receptor (GPER) in the plasma membrane is associated with excellent long-term prognosis in breast cancer. Breast Cancer Res Treat 145:61–71CrossRefPubMed

Ignatov A, Ignatov T, Roessner A, Costa SD, Kalinski T (2010) Role of GPR30 in the mechanisms of tamoxifen resistance in breast cancer MCF-7 cells. Breast Cancer Res Treat 123:87–96CrossRefPubMed

Mo Z, Liu M, Yang F et al (2013) GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer. Breast Cancer Res 15:R114CrossRefPubMedPubMedCentral

Ignatov T, Weissenborn C, Poehlmann A et al (2013) GPER-1 expression decreases during breast cancer tumorigenesis. Cancer Invest 31:309–315CrossRefPubMed

Weissenborn C, Ignatov T, Nass N et al (2017) GPER promoter methylation controls GPER expression in breast cancer patients. Cancer Invest 35:100–107CrossRefPubMed

von Elm E, Altman DG, Egger M et al (2007) The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 370:1453–1457CrossRef

Broselid S, Cheng B, Sjostrom M et al (2013) G protein-coupled estrogen receptor is apoptotic and correlates with increased distant disease-free survival of estrogen receptor-positive breast cancer patients. Clin Cancer Res 19:1681–1692CrossRefPubMed

10.

Samartzis EP, Noske A, Meisel A, Varga Z, Fink D, Imesch P (2014) The G protein-coupled estrogen receptor (GPER) is expressed in two different subcellular localizations reflecting distinct tumor properties in breast cancer. PLoS ONE 9:e83296CrossRefPubMedPubMedCentral

11.

Ariazi EA, Brailoiu E, Yerrum S et al (2010) The G protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells. Cancer Res 70:1184–1194CrossRefPubMedPubMedCentral

12.

Ignatov T, Modl S, Thulig M et al (2013) GPER-1 acts as a tumor suppressor in ovarian cancer. J Ovarian Res 6:51CrossRefPubMedPubMedCentral

13.

Liu Q, Chen Z, Jiang G et al (2017) Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer. Mol Cancer 16:87CrossRefPubMedPubMedCentral

14.

Weissenborn C, Ignatov T, Ochel HJ et al (2014) GPER functions as a tumor suppressor in triple-negative breast cancer cells. J Cancer Res Clin Oncol 140:713–723CrossRefPubMed

15.

Weissenborn C, Ignatov T, Poehlmann A et al (2014) GPER functions as a tumor suppressor in MCF-7 and SK-BR-3 breast cancer cells. J Cancer Res Clin Oncol 140:663–671CrossRefPubMed

16.

Chan QK, Lam HM, Ng CF et al (2010) Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G(2) cell-cycle arrest. Cell Death Differ 17:1511–1523CrossRefPubMedPubMedCentral

17.

Ribeiro MPC, Santos AE, Custodio JBA (2017) The activation of the G protein-coupled estrogen receptor (GPER) inhibits the proliferation of mouse melanoma K1735-M2 cells. Chem Biol Interact 277:176–184CrossRefPubMed

18.

Ignatov T, Eggemann H, Semczuk A et al (2010) Role of GPR30 in endometrial pathology after tamoxifen for breast cancer. Am J Obstet Gynecol 203:595 e9–e16CrossRef

19.

Vivacqua A, Bonofiglio D, Recchia AG et al (2006) The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17beta-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol Endocrinol 20:631–646CrossRefPubMed

Title: G-protein-coupled estrogen receptor GPER-1 expression in hormone receptor-positive breast cancer is associated with poor benefit of tamoxifen
Authors: Tanja Ignatov
Maria Claus
Norbert Nass
Johannes Haybaeck
Bernd Seifert
Thomas Kalinski
Olaf Ortmann
Atanas Ignatov
Publication date: 01-02-2019
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-5064-8

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Patients and methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2019

Plasma exosomes stimulate breast cancer metastasis through surface interactions and activation of FAK signaling

A mouse model featuring tissue-specific deletion of p53 and Brca1 gives rise to mammary tumors with genomic and transcriptomic similarities to human basal-like breast cancer

A nationwide study of breast cancer, depression, and multimorbidity among hospitalized women and men in the United States

Prognostic impact and possible pathogenesis of lymph node metastasis in ductal carcinoma in situ of the breast

Trends in use of bilateral prophylactic mastectomy vs high-risk surveillance in unaffected carriers of inherited breast cancer syndromes in the Inherited Cancer Registry (ICARE)

The impact of ethnicity on efficacy and toxicity of cyclin D kinase 4/6 inhibitors in advanced breast cancer: a meta-analysis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer