Abstract 2432: GPER1 expression is modulation by D-glucose concentration in estrogen-responsive cancer and tumor cells
Authors: Zheng Yan , Houston Kevin D. 
Published: July 2017

Abstract
G protein-coupled estrogen receptor 1 (GPER1, aka GPR30), is a 7-transmembrane receptor that mediates rapid cell signaling events stimulated by 17β-estradiol (E2) in cancer and tumor cells. In breast cancer cells, GPER1 mediates E2-induced CTGF-dependent cell migration and cyclin E expression resulting in cell cycle progression. GPER1 has also been shown to mediate antiproliferative cell signaling such as p53-dependent inhibition of cell cycle progression in breast cancer cells treated with the GPER1-specific agonist G1 and the inhibition of IGF-1R signaling in tamoxifen-treated breast cancer cells. In addition to E2, both natural and synthetic compounds have been shown to activate GPER1 in breast cancer cells. GPER1 has also been shown to regulate cell signaling in cells that lack ERα. For example, GPER1 is antiproliferative in triple-negative breast cancer cells. While the importance of GPER1 in the modulation of E2-responsive tumor and cancer cells as been demonstrated, there is very little information regarding the regulation of GPER1 expression in these cell types. The work presented here is aimed at determining the molecular mechanisms that regulate GPER1 expression. To determine if GPER1 expression is sensitive to D-glucose concentration in breast cancer cells, MCF-7 and T47D human breast cancer cells were cultured in media containing increasing concentrations of D-glucose and GPER1 expression was measured using real-time PCR and immunoblot. Data from these experiments showed that GPER1 expression was significantly increased in breast cancer cells cultured in media containing low D-glucose concentrations (0 and 2.5mM) and significantly reduced in media containing high D-glucose (25 mM). Since low D-glucose concentration is known to activate the energy-sensing AMP kinase (AMPK), the observed GPER1 induction in low D-glucose conditions was determined after pretreatment with the AMPK inhibitor compound C. GPER1 expression was inhibited in both MCF-7 and T47D breast cancer cells cultured in low D-glucose media when pretreated with compound C. Additionally, the AMPK activator metformin induced GPER1 expression in MCF-7 and T47D breast cancer cells cultured in high D-glucose (25mM) conditions. These data suggest that AMPK mediates GPER1 expression in cells cultured in low D-glucose. The D-glucose sensitivity of GPER1 expression was also determined in the Eker rat-derived uterine leiomyoma cells (ELT-3 and ELT-6) which are characterized by hyperactive AMPK. In both ELT-3 and ELT-6 cells, GPER1 expression was not sensitive to D-glucose concentration nor was the activation state of AMPK sensitive to D-glucose concentrations. However, the inhibition of AMPK by compound C in both ELT-3 and ELT-6 cells resulted in decreased GPER1 expression. These findings reveal a previously unknown mechanism that regulates GPER1 expression in E2-responsive tumor and cancer cells.
Citation Format: Yan Zheng, Kevin D. Houston. GPER1 expression is modulation by D-glucose concentration in estrogen-responsive cancer and tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2432. doi:10.1158/1538-7445.AM2017-2432