title: The human splice variant Δ16HER2 induces rapid tumor onset in a reporter transgenic mouse.
abstract: Several transgenic mice models solidly support the hypothesis that HER2 (ERBB2) overexpression or mutation promotes tumorigenesis. Recently, a HER2 splice variant lacking exon-16 (Δ16HER2) has been detected in human breast carcinomas. This alternative protein, a normal byproduct of HER2, has an increased transforming potency compared to wild-type (wt) HER2 receptors. To examine the ability of Δ16HER2 to transform mammary epithelium in vivo and to monitor Δ16HER2-driven tumorigenesis in live mice, we generated and characterized a mouse line that transgenically expresses both human Δ16HER2 and firefly luciferase under the transcriptional control of the MMTV promoter. All the transgenic females developed multifocal mammary tumors with a rapid onset and an average latency of 15.11 weeks. Immunohistochemical analysis revealed the concurrent expression of luciferase and the human Δ16HER2 oncogene only in the mammary gland and in strict correlation with tumor development. Transgenic Δ16HER2 expressed on the tumor cell plasma membrane from spontaneous mammary adenocarcinomas formed constitutively active homodimers able to activate the oncogenic signal transduction pathway mediated through Src kinase. These new transgenic animals demonstrate the ability of the human Δ16HER2 isoform to transform "per se" mammary epithelium in vivo. The high tumor incidence as well as the short latency strongly suggests that the Δ16HER2 splice variant represents the transforming form of the HER2 oncoprotein.
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Marchini
authors.forename: Federico
authors.initials: F
authors.lastname: Gabrielli
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.forename: Santa
authors.initials: S
authors.lastname: Zenobi
authors.forename: Maura
authors.initials: M
authors.lastname: Montani
authors.forename: Lucia
authors.initials: L
authors.lastname: Pietrella
authors.forename: Cristina
authors.initials: C
authors.lastname: Kalogris
authors.forename: Anna
authors.initials: A
authors.lastname: Rossini
authors.forename: Valentina
authors.initials: V
authors.lastname: Ciravolo
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Castagnoli
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
authors.forename: Serenella M
authors.initials: SM
authors.lastname: Pupa
authors.forename: Piero
authors.initials: P
authors.lastname: Musiani
authors.forename: Paolo
authors.initials: P
authors.lastname: Monaci
authors.forename: Sylvie
authors.initials: S
authors.lastname: Menard
authors.forename: Augusto
authors.initials: A
authors.lastname: Amici
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D019281:Dimerization; D004220:Disulfides; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D015674:Mammary Neoplasms, Animal; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*
chemical_list: D004220:Disulfides; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse