Abstract 4548: The role of GPR30/G-protein coupled estrogen receptor (GPER) in lung cancer development

Abstract

Abstract Lung cancer is currently the leading cause of cancer deaths both in men and women. Estrogens, including 17β-estradiol (E2), are known to promote various cancers including breast, endometrial, and ovarian cancers. Women are at higher risk for lung adenocarcinoma than men, implying a potential role for estrogens in lung cancer. E2 mediates its genomic effects through two well-characterized nuclear receptors, estrogen receptor α (ERα) and estrogen receptor β (ERβ), both of which are expressed in normal lung and lung adenocarcinomas. In addition to genomic estrogen action, i.e., transcriptional regulation of gene expression, estrogens activate rapid, non-genomic responses such as intracellular calcium release, cAMP production, MAPK and PI3K/AKT phosphorylation, and up regulation of c-fos transcription. These observations prompted a search for new estrogen receptors and culminated in the discovery of GPR30 (GPER) as a bona fide estrogen receptor that mediates some of the membrane actions of E2. GPR30 is a seven transmembrane G-protein coupled receptor (GPCR) unrelated to nuclear ERα and ERβ. Although GPR30 is expressed in healthy lung, its expression in lung tumors/lung cancer cell lines as well as its functional activities has not been investigated. In the current study, we investigated the expression of GPR30 in human and murine lung cancer cell lines and tumor tissues both at the transcript and protein levels. Our analyses demonstrated for the first time that GPR30 expression is significantly increased (2 to140 fold) in lung cancer cells lines (A549, H1435, H1395, H1944, H1792, H1793, H2073, H23, H1299, LLC) compared to immortalized normal human bronchioepithelial cells (HBEC3-ET, HBEC2-E, HBEC2-KT). The expression of GPR30 in lung tissue microarrays (LC242, LC1005 from USBiomax) containing 87 cases of lung cancer tissues along with normal and cancer adjacent tissues were analyzed by immunohistochemnistry (IHC). IHC scores confirm that GPR30 is significantly overexpressed in more than 80% of lung adenocarcinomas (p<0.0001), 75% of large cell carcinoma (p<0.0001) and 60% in squamous cell carcinoma (SCC) (p<0.0001). These observations suggest that E2, as well as other GPER ligands, signaling through GPR30 might play a critical role in lung carcinogenesis independent of the classical ERα and ERβ. Given the cross-talk between GPR30, ERα and epidermal growth factor receptor (EGFR) reported in other cell types, we suggest that blocking the signaling activities of GPR30, ERα, and EGFR may synergize to provide a better therapeutic option for treating lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4548. doi:10.1158/1538-7445.AM2011-4548