The human splice variant δ16HER2 induces rapid tumor onset in a reporter transgenic mouse

Cristina Marchini, Federico Gabrielli, Manuela Iezzi, Santa Zenobi, Maura Montani, Lucia Pietrella, Cristina Kalogris, Anna Rossini, Valentina Ciravolo, Lorenzo Castagnoli, Elda Tagliabue, Serenella M. Pupa, Piero Musiani, Paolo Monaci, Sylvie Menard, Augusto Amici

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish
Article numbere18727
JournalPLoS One
Volume6
Issue number4
DOIs
Publication statusPublished - 2011

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Transgenic Mice
Tumors
genetically modified organisms
breasts
Breast
neoplasms
mice
luciferase
Cell membranes
carcinogenesis
Neoplasms
Carcinogenesis
epithelium
Epithelium
Cell Membrane
Breast Neoplasms
Firefly Luciferases
Signal transduction
transgenic animals
Genetically Modified Animals

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Marchini, C., Gabrielli, F., Iezzi, M., Zenobi, S., Montani, M., Pietrella, L., ... Amici, A. (2011). The human splice variant δ16HER2 induces rapid tumor onset in a reporter transgenic mouse. PLoS One, 6(4), [e18727]. https://doi.org/10.1371/journal.pone.0018727

The human splice variant δ16HER2 induces rapid tumor onset in a reporter transgenic mouse. / Marchini, Cristina; Gabrielli, Federico; Iezzi, Manuela; Zenobi, Santa; Montani, Maura; Pietrella, Lucia; Kalogris, Cristina; Rossini, Anna; Ciravolo, Valentina; Castagnoli, Lorenzo; Tagliabue, Elda; Pupa, Serenella M.; Musiani, Piero; Monaci, Paolo; Menard, Sylvie; Amici, Augusto.

In: PLoS One, Vol. 6, No. 4, e18727, 2011.

Research output: Contribution to journalArticle

Marchini, C, Gabrielli, F, Iezzi, M, Zenobi, S, Montani, M, Pietrella, L, Kalogris, C, Rossini, A, Ciravolo, V, Castagnoli, L, Tagliabue, E, Pupa, SM, Musiani, P, Monaci, P, Menard, S & Amici, A 2011, 'The human splice variant δ16HER2 induces rapid tumor onset in a reporter transgenic mouse', PLoS One, vol. 6, no. 4, e18727. https://doi.org/10.1371/journal.pone.0018727
Marchini C, Gabrielli F, Iezzi M, Zenobi S, Montani M, Pietrella L et al. The human splice variant δ16HER2 induces rapid tumor onset in a reporter transgenic mouse. PLoS One. 2011;6(4). e18727. https://doi.org/10.1371/journal.pone.0018727
Marchini, Cristina ; Gabrielli, Federico ; Iezzi, Manuela ; Zenobi, Santa ; Montani, Maura ; Pietrella, Lucia ; Kalogris, Cristina ; Rossini, Anna ; Ciravolo, Valentina ; Castagnoli, Lorenzo ; Tagliabue, Elda ; Pupa, Serenella M. ; Musiani, Piero ; Monaci, Paolo ; Menard, Sylvie ; Amici, Augusto. / The human splice variant δ16HER2 induces rapid tumor onset in a reporter transgenic mouse. In: PLoS One. 2011 ; Vol. 6, No. 4.
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