GPER Mediates Activation of HIF1 α/VEGF Signaling by Estrogens

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 15; pp. 4053 - 4064
• Main Authors: DE FRANCESCO, Ernestina Marianna, PELLEGRINO, Michele, SANTOLLA, Maria Francesca, LAPPANO, Rosamaria, RICCHIO, Emilia, ABONANTE, Sergio, MAGGIOLINI, Marcello
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2014
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - blood supply; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Growth Processes - physiology; Cell Line, Tumor; Cyclopentanes - pharmacology; Estradiol - pharmacology; Estrogens - pharmacology; Female; Heterografts; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Medical sciences; Mice; Mice, Nude; Pharmacology. Drug treatments; Quinolines - pharmacology; Receptors, Estrogen - metabolism; Receptors, G-Protein-Coupled - metabolism; Signal Transduction - drug effects; Tumors; Up-Regulation - drug effects; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - metabolism; Signal transduction; Transcription factor HIF1; Vascular endothelium growth factor; Sex steroid hormone; Ovarian hormone; Estrogen
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-3590

Biological responses to estrogens in normal and malignant tissues are mainly mediated by the estrogen receptors ERα and ERβ, which function as ligand-activated transcription factors. In addition, the G protein-coupled receptor GPR30 (GPER) mediates estrogenic signaling in breast cancer cells and cancer-associated fibroblasts (CAF) that contribute to cancer progression. In this study, we evaluated the role elicited by GPER in the estrogen-regulated expression and function of vascular endothelial growth factor (VEGF) in ER-negative breast cancer cells and CAF. We demonstrated that 17β-estradiol (E2) and the GPER-selective ligand G-1 triggered a GPER/EGFR/ERK/c-fos signaling pathway that leads to increased VEGF via upregulation of HIF1α. In further extending the mechanisms involved in E2-supported angiogenesis, we also showed that conditioned medium from CAF treated with E2 and G-1 promoted human endothelial tube formation in a GPER-dependent manner. In vivo, ligand-activated GPER was sufficient to enhance tumor growth and the expression of HIF1α, VEGF, and the endothelial marker CD34 in a mouse xenograft model of breast cancer. Our findings offer important new insights into the ability of estrogenic GPER signaling to trigger HIF1α-dependent VEGF expression that supports angiogenesis and progression in breast cancer.