title: The nuclear localization signal is required for nuclear GPER translocation and function in breast Cancer-Associated Fibroblasts (CAFs).
abstract: Cancer associated fibroblasts (CAFs) actively contribute to the growth and invasion of cancer cells. In recent years, the G protein estrogen receptor (GPER) has been largely involved in the estrogenic signals in diverse types of normal and tumor cells. In CAFs, GPER was localized into the nucleus, however the molecular mechanisms which regulate its nuclear shuttle remain to be clarified. In the present study, we demonstrate that in breast CAFs GPER translocates into the nucleus through an importin-dependent mechanism. Moreover, we show that a nuclear localization signal is involved in the nuclear import of GPER, in the up-regulation of its target genes c-fos and CTGF and in the migration of CAFs induced by estrogens. Our data provide novel insights into the nuclear localization and function of GPER in CAFs toward a better understanding of the estrogen action elicited through these key players of the tumor microenvironment.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pupo
authors.forename: Adele
authors.initials: A
authors.lastname: Vivacqua
authors.forename: Ida
authors.initials: I
authors.lastname: Perrotta
authors.forename: Assunta
authors.initials: A
authors.lastname: Pisano
authors.forename: Saveria
authors.initials: S
authors.lastname: Aquila
authors.forename: Sergio
authors.initials: S
authors.lastname: Abonante
authors.forename: Anna
authors.initials: A
authors.lastname: Gasperi-Campani
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pezzi
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000737:chemistry / Q000378:metabolism*; D061251:Primary Cell Culture; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: C526317:CCN2 protein, human; D004967:Estrogens; C109584:GPER1 protein, human; D028884:Karyopherins; D019913:Nuclear Localization Signals; D016760:Proto-Oncogene Proteins c-fos; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D055513:Connective Tissue Growth Factor
keywords: Breast cancer; Cancer-associated fibroblasts; Estrogen signaling; GPER; Nuclear localization signal