Top

Published in:

Open Access 01-12-2012 | Research

GPR30 regulates the EGFR-Akt cascade and predicts lower survival in patients with ovarian cancer

Authors: Satoe Fujiwara, Yoshito Terai, Hiroshi Kawaguchi, Masaaki Takai, Saha Yoo, Yoshimichi Tanaka, Tomohito Tanaka, Satoshi Tsunetoh, Hiroshi Sasaki, Masanori Kanemura, Akiko Tanabe, Yoshiki Yamashita, Masahide Ohmichi

Published in: Journal of Ovarian Research | Issue 1/2012

Abstract

Objectives

G protein-coupled receptor 30 (GPR30) is a 7-transmembrane estrogen receptor that functions alongside traditional estrogen receptors to regulate the cellular responses to estrogen. Recent studies suggest that GPR30 expression is associated with a poor prognosis, and that this is due to the GPR30-mediated transactivation of the EGFR in breast cancer. However, the biological contribution of GPR30 in ovarian cancer remains unclear. The purpose of this study was to elucidate the relationships between GPR30 expression and the clinicopathological findings, and to determine how the signaling cascade influences the prognosis of ovarian cancer.

Methods

The expression levels of GPR30, EGFR, ERα, and ERβ were analyzed using an immunohistochemical analysis, and their correlations with the clinicopathological features were examined in 10 patients with borderline malignant tumors and 152 patients with epithelial ovarian cancer. We also examined whether GPR30 signaling activates the EGFR-Akt pathway in an ovarian cancer cell line (Caov-3) by a Western blotting analysis.

Results

The GPR30 expression in ovarian carcinomas was significantly higher than that in borderline malignancies (p=0.0016), and was not associated with the expression of the EGFR, ERα, or ERβ. The expression of GPR30 in clear cell carcinomas was significantly lower than that in other subtypes of cancer (P <; 0.001). The expression of both GPR30 and EGFR was significantly associated with a poor prognosis in terms of the progression-free survival rate. The phosphorylation of the EGFR and Akt could be significantly enhanced by G1 (p <; 0.05) and inhibited by a Src family kinase inhibitor.

Conclusion

The expression of both GPR30 and EGFR is associated with a poor outcome in ovarian cancer, and GPR30 increases the phosphorylation of Akt via the EGFR in ovarian cancer cells. The regulation of GPR30 might be a potentially useful new therapeutic target in ovarian cancer.

Available only for authorised users

Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010, 60: 277–300. 10.3322/caac.20073PubMedCrossRef

Bai W, Oliveros-Saunders B, Wang Q, Acevedo-Duncan ME, Nicosia SV: Estrogen stimulation of ovarian surface epithelial cell proliferation. In Vitro Cell Dev Biol Anim 2000, 36: 657–666. 10.1290/1071-2690(2000)036<0657:ESOOSE>2.0.CO;2PubMedCrossRef

Rodriguez C, Patel AV, Calle EE, Jacob EJ, Thun MJ: Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 2001, 285: 1460–1465. 10.1001/jama.285.11.1460PubMedCrossRef

Riman T, Dickman PW, Nilsson S, Correia N, Nordlinder H, Magnusson CM, Weiderpass E, Persson IR: Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish woman. J Natl Cancer Inst 2002, 94: 497–504. 10.1093/jnci/94.7.497PubMedCrossRef

Lacey JV Jr, Mink PJ, Lubin JH, Sherman ME, Troisi R, Hartge P, Schatzkin A, Schairer C: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002, 288: 334–341. 10.1001/jama.288.3.334PubMedCrossRef

Hall JM, Couse JF, Korach KS: The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 2001, 276: 36869–36872. 10.1074/jbc.R100029200PubMedCrossRef

Thomas P: Chemical interference with genomic and nongenomic actions of steroids in fishes: role of receptor binding. Mar Environ Res 2000, 50: 127–134. 10.1016/S0141-1136(00)00114-8PubMedCrossRef

Hiller SG, Anderson RA, Williams AR, Tetsuka M: Expression of oestrogen receptor alpha and beta in cultured human ovarian surface epithelial cells. Mol Hum Reprod 1998, 4: 811–815. 10.1093/molehr/4.8.811CrossRef

Pujol P, Rey JM, Nirde P, Roger P, Gastaldi M, Laffargue F, Rochefort H, Maudelonde T: Differential expression of estrogen receptor-alpha and –beta messenger RNAs as a potential marker of ovarian carcinogenesis. Cancer Res 1998, 58: 5367–5373.PubMed

10.

Brandenberger AW, Tee MK, Jaffe RB: Estrogen receptor alpha (ER-alpha) and beta (ER-beta) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-regulation of ER-beta in neoplastic tissues. J Clin Endocrinol Metab 1998, 83: 1025–1028. 10.1210/jc.83.3.1025PubMed

11.

Kuiper GG, Gustafsson JA: The novel estrogen receptor-beta subtype: potential role in the cell- and promoter-specific actions of estrogens and anti-estrogens. FEBS Lett 1997, 410: 87–90. 10.1016/S0014-5793(97)00413-4PubMedCrossRef

12.

Rutherford T, Brown WD, Sapi E, Aschkenazi S, Monoz A, Mor G: Absence of estrogen receptor-beta expression in metastatic ovarian cancer. Obstet Gynecol 2000, 96: 417–421. 10.1016/S0029-7844(00)00917-0PubMedCrossRef

13.

Rao BR, Slotman BJ: Endocrine factors in common epithelial ovarian cancer. Endocr Rev 1991, 12: 14–26. 10.1210/edrv-12-1-14PubMedCrossRef

14.

Hatch KD, Beecham JB, Blessing JA, Creasman WT: Responsiveness of patients with advanced ovarian carcinoma to tamoxifen. A Gynecologic Oncology Group study of second-line therapy in 105 patients. Cancer 1991, 68: 269–271. 10.1002/1097-0142(19910715)68:2<269::AID-CNCR2820680209>3.0.CO;2-OPubMedCrossRef

15.

Perez-Gracia JL, Carrasco EM: Tamoxifen therapy for ovarian cancer in the adjuvant and advanced settings: systematic review of the literature and implications for future research. Gynecol Oncol 2002, 84: 201–209. 10.1006/gyno.2001.6489PubMedCrossRef

16.

Prossnitz ER, Barton M: The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 2011, 7: 715–726. 10.1038/nrendo.2011.122PubMedCentralPubMedCrossRef

17.

Smith HO, Leslie KK, Singh M, Qualls CR, Revankar CM, Joste NE, Prossnitz ER: GPR30: a novel indicator of poor survival for endometrial carcinoma. Am J Obstet Gynecol 2007,196(4):386 e381–386 e389. discussion 386 e389–11CrossRef

18.

Albanito L, Madeo A, Lappano R, Vivacqua A, Rago V, Carpino A, Oprea TI, Prossnitz ER, Musti AM, Andò S, Maggiolini M: G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17beta-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res 2007, 67: 1859–1866. 10.1158/0008-5472.CAN-06-2909PubMedCrossRef

19.

Maggiolini M, Vivacqua A, Fasanella G, Recchia AG, Sisci D, Pezzi V, Montanaro D, Musti AM, Picard D, Andò S: The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells. J Biol Chem 2004, 279: 27008–27016. 10.1074/jbc.M403588200PubMedCrossRef

20.

Filardo EJ, Quinn JA, Bland KI, Frackelton AR Jr: Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and ocurrs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol 2000, 14: 1649–1660. 10.1210/me.14.10.1649PubMedCrossRef

21.

He YY, Cai B, Yang YX, Liu XL, Wan XP: Estrogenic G protein-coupled receptor 30 signaling is involved in regulation of endometrial carcinoma by promoting proliferation, invasion potential, and interleukin-6 secretion via the MEK/ERK mitogen-activated protein kinase pathway. Cancer Sci 2009, 100: 1051–1061. 10.1111/j.1349-7006.2009.01148.xPubMedCrossRef

22.

Filardo EJ, Graeber CT, Quinn JA, Resnick MB, Giri D, DeLellis RA, Steinhoff MM, Sabo E: 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 2006, 12: 6359–6366. 10.1158/1078-0432.CCR-06-0860PubMedCrossRef

23.

Pandey DP, Lappano R, Albanito L, Madeo A, Maggiolini M, Picard D: Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J 2009, 28: 523–532. 10.1038/emboj.2008.304PubMedCentralPubMedCrossRef

24.

Kleuser B, Malek D, Gust R, Pertz HH, Potteck H: 17-Beta-estradiol inhibits transforming growth factor-beta signaling and function in breast cancer cells via activation of extracellular signal-regulated kinase through the G protein-coupled receptor 30. Mol Pharmacol 2008, 74: 1533–1543. 10.1124/mol.108.046854PubMedCrossRef

25.

Filardo EJ: Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer. J Steroid Biochem Mol Biol 2002, 80: 231–238. 10.1016/S0960-0760(01)00190-XPubMedCrossRef

26.

Arias-Pulido H, Royce M, Gong Y, Joste N, Lomo L, Lee SJ, Chaher N, Verschraegen C, Lara J, Prossnitz ER, Cristofanilli M: GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer. Breast Cancer Res Treat 2010, 123: 51–58. 10.1007/s10549-009-0631-7PubMedCentralPubMedCrossRef

27.

Bologa CG, Revankar CM, Young SM, Edwards BS, Arterburn JB, Kiselyov AS, Parker MA, Tkachenko SE, Savchuck NP, Sklar LA, Oprea TI, Prossnitz ER: Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol 2006, 2: 207–212. 10.1038/nchembio775PubMedCrossRef

28.

Thomas P, Pang Y, Filardo EJ, Dong J: Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 2005, 146: 624–632.PubMedCrossRef

29.

Vivacqua A, Bonofiglio D, Recchia AG, Musti AM, Picard D, Andò S, Maggiolini M: The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17beta-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol Endocrinol 2006, 20: 631–646.PubMedCrossRef

30.

Berchuck A, Rodriguez GC, Kamel A, Dodge RK, Soper JT, Clarke-Pearson DL, et al.: Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. I. Correlation of receptor expression with prognostic factors in patients with ovarian cancer. Am J Obstet Gynecol 1991, 164: 669–674.PubMedCrossRef

31.

Psyrri A, Kassar M, Yu Z, Bamias A, Weinberger PM, Markakis S, Kowalski D, Camp RL, Rimm DL, Dimopoulos MA: Effect of epidermal growth factor receptor expression level on survival in patients with epithelial ovarian cancer. Clin Cancer Res 2005, 11: 8637–8643. 10.1158/1078-0432.CCR-05-1436PubMedCrossRef

32.

Vivanco I, Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002, 2: 489–501. 10.1038/nrc839PubMedCrossRef

33.

Tanaka Y, Terai Y, Tanabe A, Sasaki H, Sekijima T, Fujiwara S, Yamashita Y, Kanemura M, Ueda M, Sugita M, Franklin WA, Ohmichi M: Prognostic effect of epidermal growth factor receptor gene mutations and the aberrant phosphorylation of Akt and ERK in ovarian cancer. Cancer Biol Ther 2011, 11: 50–57. 10.4161/cbt.11.1.13877PubMedCentralPubMedCrossRef

34.

Tsunetoh S, Terai Y, Sasaki H, Tanabe A, Tanaka Y, Sekijima T, Fujioka S, Kawaguchi H, Kanemura M, Yamashita Y, Ohmichi M: Topotecan as a molecular targeting agent which blocks the Akt and VEGF cascade in platinum-resistant ovarian cancers. Cancer Biol Ther 2010, 10: 1137–1146. 10.4161/cbt.10.11.13443PubMedCentralPubMedCrossRef

35.

Smith HO, Arias-Pulido H, Kuo DY, Howard T, Qualls CR, Lee SJ, Verschraegen CF, Hathaway HJ, Joste NE, Prossnitz ER: GPR30 predicts poor survival for ovarian cancer. Gynecol Oncol 2009, 114: 465–471. 10.1016/j.ygyno.2009.05.015PubMedCentralPubMedCrossRef

36.

Syed V, Ulinski G, Mok SC, Yiu GK, Ho SM: Expression of gonadotropin receptor and growth responses to key reproductive hormones in normal and malignant human ovarian surface epithelial cells. Cancer Res 2001, 61: 6768–6776.PubMed

37.

Nash JD, Ozols RF, Smyth JF, Hamilton TC: Estrogen and anti-estrogen effects on the growth of human epithelial ovarian cancer in vitro. Obstet Gynecol 1989, 73: 1009–1016. 10.1097/00006250-198906000-00021PubMed

38.

Albanito L, Lappano R, Madeo A, Chimento A, Prossnitz ER, Cappello AR, Dolce V, Abonante S, Pezzi V, Maggiolini M: G-protein-coupled receptor 30 and estrogen receptor-alpha are involved in the proliferative effects induced by atrazine in ovarian cancer cells. Environ Health Perspect 2008, 116: 1648–1655. 10.1289/ehp.11297PubMedCentralPubMedCrossRef

39.

Guo RX, Qiao YH, Zhou Y, Li LX, Shi HR, Chen KS: Increased staining for phosphorylated AKT and nuclear factor-kappaB p65 and their relationship with prognosis in epithelial ovarian cancer. Pathol Int 2008, 58: 749–756. 10.1111/j.1440-1827.2008.02306.xPubMedCrossRef

40.

Kolkova Z, Casslen V, Henic E, Ahmadi S, Ehinger A, Jirstrom K, Casslen B: The G protein-coupled estrogen receptor 1 (GPER/GPR30) dose not predict survival in patients with ovarian cancer. J Ovarian Res 2012, 5: 9. 10.1186/1757-2215-5-9PubMedCentralPubMedCrossRef

41.

Itamochi H, Yoshida T, Walker CL, Bartholomeusz C, Aoki D, Ishihara H, Suzuki N, Kigawa J, Terakawa N, Ueno NT: Novel mechanism of reduced proliferation in ovarian clear cell carcinoma cells: cytoplasmic sequestration of CDK2 by p27. Gynecol Oncol 2011, 122: 641–647. 10.1016/j.ygyno.2011.05.003PubMedCrossRef

42.

Gilks CB: Molecular abnormalities in ovarian cancer subtypes other than high-grade serous carcinoma. J Oncol 2010. Article ID 740968

Title: GPR30 regulates the EGFR-Akt cascade and predicts lower survival in patients with ovarian cancer
Authors: Satoe Fujiwara
Yoshito Terai
Hiroshi Kawaguchi
Masaaki Takai
Saha Yoo
Yoshimichi Tanaka
Tomohito Tanaka
Satoshi Tsunetoh
Hiroshi Sasaki
Masanori Kanemura
Akiko Tanabe
Yoshiki Yamashita
Masahide Ohmichi
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Ovarian Research / Issue 1/2012
Electronic ISSN: 1757-2215
DOI: https://doi.org/10.1186/1757-2215-5-35

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

GPR30 regulates the EGFR-Akt cascade and predicts lower survival in patients with ovarian cancer

Abstract

Objectives

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Objectives

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2012

Relevance of immunohistochemical expression of p57kip2 in epithelial ovarian carcinoma- A systematic literature review

Clinical outcome of fresh and vitrified-warmed blastocyst and cleavage-stage embryo transfers in ethnic Chinese ART patients

Tubal ligation, hysterectomy and ovarian cancer: A meta-analysis

Mucinous adenocarcinoma of the intestinal type arising from mature cystic teratoma of the ovary: a rare case report and review of the literature

Thailandepsins are new small molecule class I HDAC inhibitors with potent cytotoxic activity in ovarian cancer cells: a preclinical study of epigenetic ovarian cancer therapy

IGFBP-4 tumor and serum levels are increased across all stages of epithelial ovarian cancer