Oncotarget

Research Papers:

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

Arianna 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 M. Pupa, Carla De Giovanni, Elda Tagliabue, Manuela Iezzi, Patrizia Nanni _ and Pier-Luigi Lollini

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Oncotarget. 2017; 8:54444-54458. https://doi.org/10.18632/oncotarget.17088

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Abstract

Arianna Palladini1,*, Giordano Nicoletti2,*, Alessia Lamolinara3,*, Massimiliano Dall’Ora1,*, Tania Balboni1, Marianna L. Ianzano1, Roberta Laranga1, Lorena Landuzzi2, Veronica Giusti1, Claudio Ceccarelli1,4, Donatella Santini4, Mario Taffurelli5, Enrico Di Oto6, Sofia Asioli6, Augusto Amici7, Serenella M. Pupa8, Carla De Giovanni1, Elda Tagliabue8, Manuela Iezzi3, Patrizia Nanni1 and Pier-Luigi Lollini1

1Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

2Rizzoli Orthopedic Institute, Laboratory of Experimental Oncology, Bologna, Italy

3Aging Research Centre, “Gabriele d’Annunzio” University, Chieti, Italy

4Pathology Unit, Policlinico S.Orsola-Malpighi University Hospital, Bologna, Italy

5Department of Medical and Surgical Sciences of Bologna, Bologna, Italy

6Anatomic Pathology, Department of Biomedical and Neuromotor Sciences, Bellaria Hospital, University of Bologna, Bologna, Italy

7University of Camerino, Camerino, Italy

8Istituto Nazionale Tumori, Milano, Italy

*These authors have contributed equally to this work

Correspondence to:

Patrizia Nanni, email: [email protected]

Keywords: HER2, Delta16, trastuzumab, breast cancer, model of host-tumor interactions

Received: December 16, 2016    Accepted: March 22, 2017    Published: April 13, 2017

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.


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