title: EFA6B antagonizes breast cancer.
abstract: One of the earliest events in epithelial carcinogenesis is the dissolution of tight junctions and cell polarity signals that are essential for normal epithelial barrier function. Here, we report that EFA6B, a guanine nucleotide exchange factor for the Ras superfamily protein Arf6 that helps assemble and stabilize tight junction, is required to maintain apico-basal cell polarity and mesenchymal phenotypes in mammary epithelial cells. In organotypic three-dimensional cell cultures, endogenous levels of EFA6B were critical to determine epithelial-mesenchymal status. EFA6B downregulation correlated with a mesenchymal phenotype and ectopic expression of EFA6B hampered TGFβ-induced epithelial-to-mesenchymal transition (EMT). Transcriptomic and immunohistochemical analyses of human breast tumors revealed that the reduced expression of EFA6B was associated with loss of tight junction components and with increased signatures of EMT, cancer stemness, and poor prognosis. Accordingly, tumors with low levels of EFA6B were enriched in the aggressive triple-negative and claudin-low breast cancer subtypes. Our results identify EFA6B as a novel antagonist in breast cancer and they point to its regulatory and signaling pathways as rational therapeutic targets in aggressive forms of this disease.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia-Antipolis CNRS UMR7275, Valbonne, France.
authors.forename: Joséphine
authors.initials: J
authors.lastname: Zangari
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia-Antipolis CNRS UMR7275, Valbonne, France.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Partisani
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, Institut Paoli-Calmettes, CNRS UMR7258, Aix-Marseille Université, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia-Antipolis CNRS UMR7275, Valbonne, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Milanini
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, Institut Paoli-Calmettes, CNRS UMR7258, Aix-Marseille Université, Marseille, France.
authors.forename: Ghislain
authors.initials: G
authors.lastname: Bidaut
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, Institut Paoli-Calmettes, CNRS UMR7258, Aix-Marseille Université, Marseille, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Berruyer-Pouyet
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, Institut Paoli-Calmettes, CNRS UMR7258, Aix-Marseille Université, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Laboratoire de Pathologie Clinique et Expérimentale et biobanque CHUN, Nice, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Long
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia-Antipolis CNRS UMR7275, Valbonne, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Brau
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, Institut Paoli-Calmettes, CNRS UMR7258, Aix-Marseille Université, Marseille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cabaud
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, Institut Paoli-Calmettes, CNRS UMR7258, Aix-Marseille Université, Marseille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Chetaille
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, Institut Paoli-Calmettes, CNRS UMR7258, Aix-Marseille Université, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, Institut Paoli-Calmettes, CNRS UMR7258, Aix-Marseille Université, Marseille, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lopez
authors.affiliation: Laboratoire de Pathologie Clinique et Expérimentale et biobanque CHUN, Nice, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia-Antipolis CNRS UMR7275, Valbonne, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Franco
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia-Antipolis CNRS UMR7275, Valbonne, France. luton@ipmc.cnrs.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Luton
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D062465:Claudin-3 / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D019108:Tight Junctions / Q000502:physiology
chemical_list: D062465:Claudin-3; D020662:Guanine Nucleotide Exchange Factors; C000595709:PSD4 protein, human; D012333:RNA, Messenger