title: GPER mediates the Egr-1 expression induced by 17β-estradiol and 4-hydroxitamoxifen in breast and endometrial cancer cells.
abstract: Early growth response-1 (Egr-1) is an immediate early gene involved in relevant biological events including the proliferation of diverse types of cell tumors. In a microarray analysis performed in breast cancer cells, 17β-estradiol (E2) and the estrogen receptor antagonist 4-hydroxitamoxifen (OHT) up-regulated Egr-1 through the G protein-coupled receptor named GPR30/GPER. Hence, in this study, we aimed to provide evidence regarding the ability of E2, OHT and the selective GPER ligand G-1 to regulate Egr-1 expression and function through the GPER/EGFR/ERK transduction pathway in both Ishikawa (endometrial) and SkBr3 (breast) cancer cells. Interestingly, we demonstrate that Egr-1 is involved in the transcription of genes regulating cell proliferation like CTGF and cyclin D1 and required for the proliferative effects induced by E2, OHT, and G-1 in both Ishikawa and SkBr3 cells. In addition, we show that GPER mediates the expression of Egr-1 also in carcinoma-associated fibroblasts (CAFs). Our data suggest that Egr-1 may represent an important mediator of the biological effects induced by E2 and OHT through GPER/EGFR/ERK signaling in breast and endometrial cancer cells. The results obtained in CAFs provide further evidence regarding the potential role exerted by the GPER-dependent Egr-1 up-regulation in tumor development and progression. Therefore, Egr-1 may be included among the bio-markers of estrogen and antiestrogen actions and may be considered as a further therapeutic target in both breast and endometrial tumors.
authors.affiliation: Department of Pharmaco-Biology, University of Calabria, 87030 Rende, CS, Italy. adelevivacqua@yahoo.it
authors.forename: Adele
authors.initials: A
authors.lastname: Vivacqua
authors.forename: Enrica
authors.initials: E
authors.lastname: Romeo
authors.forename: Paola
authors.initials: P
authors.lastname: De Marco
authors.forename: Ernestina Marianna
authors.initials: EM
authors.lastname: De Francesco
authors.forename: Sergio
authors.initials: S
authors.lastname: Abonante
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000235:genetics* / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D051766:Early Growth Response Protein 1; D004965:Estrogen Antagonists; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D013629:Tamoxifen; D019938:Cyclin D1; D055513:Connective Tissue Growth Factor; C016601:afimoxifene; D004958:Estradiol; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases