title: GPER mediates activation of HIF1α/VEGF signaling by estrogens.
abstract: 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.
authors.affiliation: Department of Pharmacy, Health and Nutrition Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Ernestina Marianna
authors.initials: EM
authors.lastname: De Francesco
authors.affiliation: Department of Pharmacy, Health and Nutrition Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Pellegrino
authors.affiliation: Department of Pharmacy, Health and Nutrition Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Santolla
authors.affiliation: Department of Pharmacy, Health and Nutrition Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Lappano
authors.affiliation: Department of Pharmacy, Health and Nutrition Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Ricchio
authors.affiliation: Regional Hospital, Cosenza, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Abonante
authors.affiliation: Department of Pharmacy, Health and Nutrition Sciences, University of Calabria, Rende (CS), Italy. marcellomaggiolini@yahoo.it.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011804:Quinolines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D003517:Cyclopentanes; D004967:Estrogens; C109584:GPER1 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol