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 NanniPier Luigi Lollini

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 fulllength 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 patientderived 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 - Jan 1 2017

Fingerprint

Protein Isoforms
Breast Neoplasms
Phenotype
Neoplasms
Therapeutics
Transgenic Mice
Oncogene Proteins
Growth
Heterografts
Doxorubicin
Vascular Endothelial Growth Factor A
Endothelium
Blood Vessels
Transplants

Keywords

  • Animal models of cancer
  • Breast cancer
  • Delta16
  • HER2
  • Model of host-tumor interactions
  • Trastuzumab

ASJC Scopus subject areas

  • Oncology

Cite this

HER2 isoforms co-expression differently tunes mammary tumor phenotypes affecting onset, vasculature and therapeutic response. / Palladini, Arianna; Nicoletti, Giordano; Lamolinara, Alessia; Dall'Ora, Massimiliano; Balboni, Tania; Ianzano, Marianna L.; Laranga, Roberta; Landuzzi, Lorena; Giusti, Veronica; Ceccarelli, Claudio; Santini, Donatella; Taffurelli, Mario; Oto, Enrico Di; Asioli, Sofia; Amici, Augusto; Pupa, Serenella M.; De Giovanni, Carla; Tagliabue, Elda; Iezzi, Manuela; Nanni, Patrizia; Lollini, Pier Luigi.

In: Oncotarget, Vol. 8, No. 33, 01.01.2017, p. 54444-54458.

Research output: Contribution to journalArticle

Palladini, A, Nicoletti, G, Lamolinara, A, Dall'Ora, M, Balboni, T, Ianzano, ML, Laranga, R, Landuzzi, L, Giusti, V, Ceccarelli, C, Santini, D, Taffurelli, M, Oto, ED, Asioli, S, Amici, A, Pupa, SM, De Giovanni, C, Tagliabue, E, Iezzi, M, Nanni, P & Lollini, PL 2017, 'HER2 isoforms co-expression differently tunes mammary tumor phenotypes affecting onset, vasculature and therapeutic response', Oncotarget, vol. 8, no. 33, pp. 54444-54458. https://doi.org/10.18632/oncotarget.17088
Palladini, Arianna ; Nicoletti, Giordano ; Lamolinara, Alessia ; Dall'Ora, Massimiliano ; Balboni, Tania ; Ianzano, Marianna L. ; Laranga, Roberta ; Landuzzi, Lorena ; Giusti, Veronica ; Ceccarelli, Claudio ; Santini, Donatella ; Taffurelli, Mario ; Oto, Enrico Di ; Asioli, Sofia ; Amici, Augusto ; Pupa, Serenella M. ; De Giovanni, Carla ; Tagliabue, Elda ; Iezzi, Manuela ; Nanni, Patrizia ; Lollini, Pier Luigi. / HER2 isoforms co-expression differently tunes mammary tumor phenotypes affecting onset, vasculature and therapeutic response. In: Oncotarget. 2017 ; Vol. 8, No. 33. pp. 54444-54458.
@article{3fc2a1396658487496b2fe0ba6c2292f,
title = "HER2 isoforms co-expression differently tunes mammary tumor phenotypes affecting onset, vasculature and therapeutic response",
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 fulllength 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 patientderived xenografts, for studies of mammary carcinoma onset, prevention and therapy.",
keywords = "Animal models of cancer, Breast cancer, Delta16, HER2, Model of host-tumor interactions, Trastuzumab",
author = "Arianna Palladini and Giordano Nicoletti and Alessia Lamolinara and Massimiliano Dall'Ora and Tania Balboni and Ianzano, {Marianna L.} and Roberta Laranga and Lorena Landuzzi and Veronica Giusti and Claudio Ceccarelli and Donatella Santini and Mario Taffurelli and Oto, {Enrico Di} and Sofia Asioli and Augusto Amici and Pupa, {Serenella M.} and {De Giovanni}, Carla and Elda Tagliabue and Manuela Iezzi and Patrizia Nanni and Lollini, {Pier Luigi}",
year = "2017",
month = "1",
day = "1",
doi = "10.18632/oncotarget.17088",
language = "English",
volume = "8",
pages = "54444--54458",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "33",

}

TY - JOUR

T1 - HER2 isoforms co-expression differently tunes mammary tumor phenotypes affecting onset, vasculature and therapeutic response

AU - Palladini, Arianna

AU - Nicoletti, Giordano

AU - Lamolinara, Alessia

AU - Dall'Ora, Massimiliano

AU - Balboni, Tania

AU - Ianzano, Marianna L.

AU - Laranga, Roberta

AU - Landuzzi, Lorena

AU - Giusti, Veronica

AU - Ceccarelli, Claudio

AU - Santini, Donatella

AU - Taffurelli, Mario

AU - Oto, Enrico Di

AU - Asioli, Sofia

AU - Amici, Augusto

AU - Pupa, Serenella M.

AU - De Giovanni, Carla

AU - Tagliabue, Elda

AU - Iezzi, Manuela

AU - Nanni, Patrizia

AU - Lollini, Pier Luigi

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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 fulllength 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 patientderived xenografts, for studies of mammary carcinoma onset, prevention and therapy.

AB - 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 fulllength 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 patientderived xenografts, for studies of mammary carcinoma onset, prevention and therapy.

KW - Animal models of cancer

KW - Breast cancer

KW - Delta16

KW - HER2

KW - Model of host-tumor interactions

KW - Trastuzumab

UR - http://www.scopus.com/inward/record.url?scp=85029072928&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029072928&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.17088

DO - 10.18632/oncotarget.17088

M3 - Article

AN - SCOPUS:85029072928

VL - 8

SP - 54444

EP - 54458

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 33

ER -