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

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

Description

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.

Sujets

• GPR30
• EGFR
• AKT

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 7
• Langue: English

Extrait

Fujiwaraet al. Journal of Ovarian Research2012,5:35 http://www.ovarianresearch.com/content/5/1/35

R E S E A R C HOpen Access GPR30 regulates the EGFRAkt cascade and predicts lower survival in patients with ovarian cancer * Satoe Fujiwara, Yoshito Terai , Hiroshi Kawaguchi, Masaaki Takai, Saha Yoo, Yoshimichi Tanaka, Tomohito Tanaka, Satoshi Tsunetoh, Hiroshi Sasaki, Masanori Kanemura, Akiko Tanabe, Yoshiki Yamashita and Masahide Ohmichi

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 ERβwere 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. Keywords:G proteincoupled receptor 30, GPR30, 7transmembrane estrogen receptor, EGFR, Akt, ERα; Clear cell carcinomas, Prognostic factor

Introduction Ovarian cancer is the most common cause of gynecological cancerrelated death. Approximately 70% of all patients with ovarian cancer are diagnosed at an advanced stage, and 60% to 80% of patients die of the disease [1]. The main reasons for the poor prognosis are the high recurrence rate and resistance to secondline chemotherapeutics. Therefore, the development of new

* Correspondence: y[e-mail]med.ac.jp Department of Obstetrics and Gynecology, Osaka Medical College, 27, Daigakumachi, Takatsuki, Osaka 5698686, Japan

therapies is critical for the treatment of ovarian cancer patients. Estrogens are major regulators of growth and differen tiation in the normal ovaries, and also play an important role in the progression of ovarian cancer. Likewise, a marked proliferative response to estrogens was shown in ovarian surface epithelial cells, which are the site of 90% of malignancies [2], and an increased risk of ovarian tumors was observed in postmenopausal patients receiv ing estrogen replacement therapy [35]. The biological effects of estrogens are classically mediated by the

© 2012 Fujiwara et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.