title: Shed HER2 extracellular domain in HER2-mediated tumor growth and in trastuzumab susceptibility.
abstract: The question of the serum HER2 extracellular domain (HER2/ECD) measurement for prediction of response to the anti-HER2 antibody Trastuzumab is still an open and current matter of clinical debate. To elucidate the involvement of shed HER2/ECD in HER2-driven tumor progression and in guiding therapy of individual patients, we examined biological effects exerted by elevated HER2/ECD in cancer growth and in response to Trastuzumab. To this purpose SKOV3 tumor cells were stably transfected to release a recombinant HER2/ECD molecule (rECD). Transfectants releasing high levels of 110-kDa rECD, identical in size to native HER2/ECD (nECD), grew significantly slower than did controls, which constitutively released only basal levels of nECD. While transmembrane HER2 and HER1 were expressed at equal levels by both controls and transfected cells, activation of these molecules and of downstream ERK2 and Akt was significantly reduced only in rECD transfectants. Surface plasmon resonance analysis revealed heterodimerization of the rECD with HER1, -2, and -3. In cell growth bioassays in vitro, shed HER2 significantly blocked HER2-driven tumor cell proliferation. In mice, high levels of circulating rECD significantly impaired HER2-driven SKOV3 tumor growth but not that of HER2-negative tumor cells. In vitro and in mice, Trastuzumab significantly inhibited tumor growth due to the rECD-facilitated accumulation of the antibody on tumor cells. Globally our findings sustain the biological relevance of elevated HER2/ECD levels in the outcome of HER2-disease and in the susceptibility to Trastuzumab-based therapy.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Gaia C
authors.initials: GC
authors.lastname: Ghedini
authors.forename: Valentina
authors.initials: V
authors.lastname: Ciravolo
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.forename: Sarah
authors.initials: S
authors.lastname: Giuffrè
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchi
authors.forename: Manuela
authors.initials: M
authors.lastname: Campiglio
authors.forename: Mimosa
authors.initials: M
authors.lastname: Mortarino
authors.forename: Mariangela
authors.initials: M
authors.lastname: Figini
authors.forename: Angela
authors.initials: A
authors.lastname: Coliva
authors.forename: Maria L
authors.initials: ML
authors.lastname: Carcangiu
authors.forename: Milvia
authors.initials: M
authors.lastname: Zambetti
authors.forename: Tiziana
authors.initials: T
authors.lastname: Piazza
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ménard
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
authors.forename: Serenella M
authors.initials: SM
authors.lastname: Pupa
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab