title: Transmembrane domain targeting peptide antagonizing ErbB2/Neu inhibits breast tumor growth and metastasis.
abstract: Breast cancer is still a deadly disease despite major achievements in targeted therapies designed to block ligands or ligand-binding subunits of major tyrosine kinase receptors. Relapse is significant and metastases deleterious, which demands novel strategies for fighting this disease. Here, we report a proof-of-concept experiment demonstrating that small peptides interfering with the transmembrane domain of the tyrosine kinase epidermal growth factor receptor ErbB2 exhibit anticancer properties when used at micromolar dosages in a genetically engineered mouse model of breast cancer. Different assays demonstrate the specificity of the ErbB2-targeting peptide, which induces long-term reduction of ErbB2 phosphorylation and Akt signaling consistent with reduced tumor cell proliferation and increased survival. Microcomputed tomography analysis established the antimetastatic activity of the peptide and its impact on primary tumor growth. This reveals the interior of the cell membrane as an unexplored dimension for drug design.
authors.affiliation: INSERM U 1109, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg 67200, France; CNRS UMR 7178, Institut Pluridisciplinaire Hubert Curien, Strasbourg University, Strasbourg 67037, France.
authors.forename: Alexia
authors.initials: A
authors.lastname: Arpel
authors.affiliation: CNRS LISM UMR 7255, Aix Marseille University, Marseille 13402, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Sawma
authors.affiliation: INSERM U 1109, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg 67200, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Spenlé
authors.affiliation: INSERM U 1109, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg 67200, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Fritz
authors.affiliation: INSERM U 1109, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg 67200, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Meyer
authors.affiliation: CNRS UPR 4301, Centre de Biophysique Moléculaire (CBM), Orleans University, Orleans F-45071, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Garnier
authors.affiliation: INSERM U 1109, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg 67200, France.
authors.forename: Inés
authors.initials: I
authors.lastname: Velázquez-Quesada
authors.affiliation: INSERM U 1109, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg 67200, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hussenet
authors.affiliation: CNRS UPR 4301, Centre de Biophysique Moléculaire (CBM), Orleans University, Orleans F-45071, France; ICOA UMR 7311, Orleans University, Orleans 45100, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Aci-Sèche
authors.affiliation: INSERM U 1109, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg 67200, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Baumlin
authors.affiliation: CNRS UPR 4301, Centre de Biophysique Moléculaire (CBM), Orleans University, Orleans F-45071, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Genest
authors.affiliation: CNRS UMR 7178, Institut Pluridisciplinaire Hubert Curien, Strasbourg University, Strasbourg 67037, France.
authors.forename: David
authors.initials: D
authors.lastname: Brasse
authors.affiliation: CNRS LISM UMR 7255, Aix Marseille University, Marseille 13402, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hubert
authors.affiliation: INSERM U 1109, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg 67200, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Crémel
authors.affiliation: INSERM U 1109, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg 67200, France.
authors.forename: Gertraud
authors.initials: G
authors.lastname: Orend
authors.affiliation: CNRS UMR 7178, Institut Pluridisciplinaire Hubert Curien, Strasbourg University, Strasbourg 67037, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Laquerrière
authors.affiliation: INSERM U 1109, Labex Medalis, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg 67200, France. Electronic address: bagnard@unistra.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bagnard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000556:secondary; D061986:MCF-7 Cells; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014057:Tomography, X-Ray Computed
chemical_list: D010455:Peptides; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases