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

Arianna Palladini,Roberta Laranga,Claudio Ceccarelli,Marianna L Ianzano,Alessia Lamolinara,Enrico Di Oto,Lorena Landuzzi,Sofia Asioli,Serenella M Pupa,Patrizia Nanni,Manuela Iezzi,Augusto Amici,Tania Balboni,Veronica Giusti,Donatella Santini,Mario Taffurelli,Carla De Giovanni,Massimiliano Dall’Ora,Giordano Nicoletti,Elda Tagliabue,Pier‐Luigi Lollini

doi:10.18632/oncotarget.17088

Arianna Palladini, Roberta Laranga + Show 19 more

Open Access

PDF Available

https://doi.org/10.18632/oncotarget.17088

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

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.

Highlights

The HER2 oncogene encodes a tyrosine kinase involved in the onset and progression of breast cancer and other human tumors [1,2,3,4]
Mammary carcinogenesis was slow in transgenic mice carrying the full-length human HER2 gene: the earliest mammary carcinomas appeared around 30 weeks of age, tumor incidence reached 100% well beyond one year of age (Figure 1A)
Mammary carcinomas of F1 HER2/Delta16 mice presented both types of vascularization (Supplementary Figure 2), when we classified the tumors by the prevalent HER2 isoform expressed, we found that tumors with high full-length HER2 expression showed few large vessels (Figure 3E and 3F), whereas tumors with low full-length HER2 and high Delta16 mainly contained numerous small vessels

Summary

Introduction

The HER2 oncogene encodes a tyrosine kinase involved in the onset and progression of breast cancer and other human tumors [1,2,3,4]. Tumor cells may contain at the same time different HER2 proteins resulting from mutation, alternative splicing, alternative initiation of translation and post-translational modification [4,5,6,7,8,9,10,11,12,13,14,15]. The Delta splice variant, lacking exon 16, has the properties of an activated oncogene [5,6,7, 10, 17,18,19,20] and its expression was recently found to be associated with high stemness and epithelial mesenchymal transition [20, 21]. Delta could play beneficial roles in the response to targeted therapeutic agents, such as the monoclonal antibody trastuzumab [18, 19]

Methods

Results

Conclusion