HER2 isoforms co-expression differently tunes mammary tumor phenotypes affecting onset, vasculature and therapeutic response

Ariannna Palladini, Giordano Nicoletti, Alessia Lamolinara, Massimiliano Dall'Ora, tania Balboni, Marianna L. Ianzano, Roberta Laranga, Lorena Landuzzi, Veronica Giusti, Claudio Ceccarelli, Donatella Santini, Mario Taffurelli, Enrico Di Oto, Sofia Asioli, Augusto Amici, Serenella Pupa, Carla De Giovanni, Elda Tagliabue, Manuela Iezzi, Patrizia NanniPier Luigi Lollini

Research output: Contribution to journalArticle

Abstract

Full-length HER2 oncoprotein and splice variant Delta16 are co-expressed in human breast cancer. We studied their interaction in hybrid transgenic mice bearing human full-length HER2 and Delta16 (F1 HER2/Delta16) in comparison to parental HER2 and Delta16 transgenic mice. Mammary carcinomas onset was faster in F1 HER2/Delta16 and Delta16 than in HER2 mice, however tumor growth was slower, and metastatic spread was comparable in all transgenic mice. Full-length HER2 tumors contained few large vessels or vascular lacunae, whereas Delta16 tumors presented a more regular vascularization with numerous endothelium-lined small vessels. Delta16-expressing tumors showed a higher accumulation of i.v. injected doxorubicin than tumors expressing full-length HER2. F1 HER2/Delta16 tumors with high full-length HER2 expression made few large vessels, whereas tumors with low full-length HER2 and high Delta16 contained numerous small vessels and expressed higher levels of VEGF and VEGFR2. Trastuzumab strongly inhibited tumor onset in F1 HER2/Delta16 and Delta16 mice, but not in full-length HER2 mice. Addiction of F1 tumors to Delta16 was also shown by long-term stability of Delta16 levels during serial transplants, in contrast full-length HER2 levels underwent wide fluctuations. In conclusion, full-length HER2 leads to a faster tumor growth and to an irregular vascularization, whereas Delta16 leads to a faster tumor onset, with more regular vessels, which in turn could better transport cytotoxic drugs within the tumor, and to a higher sensitivity to targeted therapeutic agents. F1 HER2/Delta16 mice are a new immunocompetent mouse model, complementary to patient-derived xenografts, for studies of mammary carcinoma onset, prevention and therapy.
Original languageEnglish
Pages (from-to)54444-54458
Number of pages15
JournalOncotarget
Volume8
Issue number33
DOIs
Publication statusPublished - Apr 13 2017

Keywords

  • Delta16
  • HER2
  • animal models of cancer
  • breast cancer
  • model of host-tumor interactions
  • trastuzumab

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    Palladini, A., Nicoletti, G., Lamolinara, A., Dall'Ora, M., Balboni, T., Ianzano, M. L., Laranga, R., Landuzzi, L., Giusti, V., Ceccarelli, C., Santini, D., Taffurelli, M., Di Oto, E., Asioli, S., Amici, A., Pupa, S., De Giovanni, C., Tagliabue, E., Iezzi, M., ... Lollini, P. L. (2017). HER2 isoforms co-expression differently tunes mammary tumor phenotypes affecting onset, vasculature and therapeutic response. Oncotarget, 8(33), 54444-54458. https://doi.org/10.18632/oncotarget.17088