GPER functions as a tumor suppressor in MCF-7 and SK-BR-3 breast cancer cells
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The orphan, membrane-bound estrogen receptor (GPER) is expressed at high levels in a large fraction of breast cancer patients, and its expression is favorable for patients’ survival. We investigated the role of GPER as a potential tumor suppressor in MCF-7 and SK-BR-3 breast cancer cells.
The effect of GPER agonist G-1 in cell culture was used to determine whether GPER inhibit cell growth. The methylation status of GPER promoter was investigated by methylation-specific PCR.
GPER-specific agonist G-1 inhibited breast cancer cell proliferation in concentration-dependent manner via induction of the cell cycle arrest in M-phase, enhanced phosphorylation of histone 3 and cell apoptosis. Analysis of the methylation status of the GPER promoter in MCF-7 and SK-BR-3 cells revealed that GPER expression is regulated by epigenetic mechanisms and GPER expression is inactivated by promoter methylation. Overall, our results are consistent with our recent findings in triple-negative breast cancer cells, and the cell surface expression of GPER makes it an excellent potential therapeutic target for non-triple-negative breast cancer.
KeywordsGPER GPR30 Breast cancer Tumor suppressor
This work was supported by Deutsche Krebshilfe to AI.
Conflict of interest
We declare that we have no conflict of interest.
- Albanito L, Madeo A, Lappano R, Vivacqua A, Rago V, Carpino A, Oprea TI, Prossnitz ER, Musti AM, Ando S, Maggiolini M (2007) G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17 beta-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res 67:1859–1866CrossRefPubMedGoogle Scholar
- 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 149:3799–3808CrossRefPubMedCentralPubMedGoogle Scholar
- Arias-Pulido H, Royce M, Gong Y, Joste N, Lomo L, Lee SJ, Chaher N, Verschraegen C, Lara J, Prossnitz ER, Cristofanilli M (2010) GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer. Breast Cancer Res Treat 123:51–58CrossRefPubMedCentralPubMedGoogle Scholar
- 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 70:1184–1194CrossRefPubMedCentralPubMedGoogle Scholar
- Chan QK, Lam HM, Ng CF, Lee AY, Chan ES, Ng HK, Ho SM, Lau KM (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 17:1511–1523CrossRefPubMedCentralPubMedGoogle Scholar
- De Marco P, Bartella V, Vivacqua A, Lappano R, Santolla MF, Morcavallo A, Pezzi V, Belfiore A, Maggiolini M (2012) Insulin-like growth factor-I regulates GPER expression and function in cancer cells. Oncogene 32(6):678–688Google Scholar
- 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
- 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
- Ignatov A, Lintzel J, Kreienkamp HJ, Schaller HC (2003) Sphingosine-1-phosphate is a high-affinity ligand for the G protein-coupled receptor GPR6 from mouse and induces intracellular Ca2+ release by activating the sphingosine-kinase pathway. Biochem Biophys Res Commun 311:329–336CrossRefPubMedGoogle Scholar
- Ignatov A, Bischoff J, Ignatov T, Schwarzenau C, Krebs T, Kuester D, Costa SD, Roessner A, Semczuk A, Schneider-Stock R (2009a) APC promoter hypermethylation is an early event in endometrial tumorigenesis. Cancer Sci 101(2):321–327Google Scholar
- Ignatov A, Ignatov T, Roessner A, Costa SD, Kalinski T (2009b) Role of GPR30 in the mechanisms of tamoxifen resistance in breast cancer MCF-7 cells. Breast Cancer Res Treat 123(1):87–96Google Scholar
- 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 46:135–145CrossRefPubMedGoogle Scholar
- 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
- Maggiolini M, Vivacqua A, Fasanella G, Recchia AG, Sisci D, Pezzi V, Montanaro D, Musti AM, Picard D, Ando S (2004) The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17 beta-estradiol and phytoestrogens in breast cancer cells. J Biol Chem 279:27008–27016CrossRefPubMedGoogle Scholar
- Poola I, Abraham J, Liu A, Marshalleck JJ, Dewitty RL (2008) The cell surface estrogen receptor, G protein- coupled receptor 30 (GPR30), is markedly down regulated during breast tumorigenesis. Breast Cancer (Auckl) 1:65–78Google Scholar
- Schumacher A, Brachwitz N, Sohr S, Engeland K, Langwisch S, Dolaptchieva M, Alexander T, Taran A, Malfertheiner SF, Costa SD, Zimmermann G, Nitschke C, Volk HD, Alexander H, Gunzer M, Zenclussen AC (2009) Human chorionic gonadotropin attracts regulatory T cells into the fetal-maternal interface during early human pregnancy. J Immunol 182:5488–5497CrossRefPubMedGoogle Scholar