Oncotarget

Research Papers:

Activation of EGFR, HER2 and HER3 by neurotensin/neurotensin receptor 1 renders breast tumors aggressive yet highly responsive to lapatinib and metformin in mice

Sandra Dupouy, Van Kien Doan, Zherui Wu, Najat Mourra, Olivier De Wever, Frédérique Penault Llorca, Anne Cayre, Amal Kouchkar, Anne Gompel and Patricia Forgez _

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Oncotarget. 2014; 5:8235-8251. https://doi.org/10.18632/oncotarget.1632

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Abstract

Sandra Dupouy1,*, Van Kien Doan1,*, Zherui Wu1,2,*, Najat Mourra1,3, Jin Liu2, Olivier De Wever4, Frédérique Penault Llorca5, Anne Cayre5, Amal Kouchkar6, Anne Gompel2,7, Patricia Forgez2

1UMRS U938, Hôpital Saint-Antoine, Paris, France

2UMRS 1007 Université Paris Descartes 45, Paris, France

3Pathology Department Hôpital Saint-Antoine, Paris, France

4The Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium

5Pathology Department, Jean Perrin Center, Clermont Ferrand, France

6Pathology Department, Alger Pierre and Marie Curie Center, Algeria

7Gynecology Unit, Université Paris Descartes, APHP, Hôpitaux Universitaires Cochin Hôtel-Dieu Broca, Paris, France

*SD, VKD, and ZW contributed equally to this work.

Correspondence to:

Patricia Forgez, e-mail: [email protected]

Keywords: Cancer growth and metastasis, neurotensin, EGFR, HER2, HER3, EGF like ligands

Received: November 28, 2013     Accepted: May 7, 2014      Published: October 03, 2014

ABSTRACT

A present challenge in breast oncology research is to identify therapeutical targets which could impact tumor progression. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 20% of breast cancers, and NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in invasive breast carcinomas. Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here, we depict the cellular mechanisms activated by NTS, and contributing to breast cancer cell aggressiveness.

We show that neurotensin (NTS) and its high affinity receptor (NTSR1) contribute to the enhancement of experimental tumor growth and metastasis emergence in an experimental mice model. This effect ensued following EGFR, HER2, and HER3 over-expression and autocrine activation and was associated with an increase of metalloproteinase MMP9, HB-EGF and Neuregulin 2 in the culture media. EGFR over expression ensued in a more intense response to EGF on cellular migration and invasion. Accordingly, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, as well as metformin, reduced the tumor growth of cells overexpressing NTS and NTSR1. All cellular effects, such as adherence, migration, invasion, altered by NTS/NTSR1 were abolished by a specific NTSR1 antagonist. A strong statistical correlation between NTS-NTSR1-and HER3 (p< 0.0001) as well as NTS-NTSR1-and HER3- HER2 (p< 0.001) expression was found in human breast tumors.

Expression of NTS/NTSR1 on breast tumoral cells creates a cellular context associated with cancer aggressiveness by enhancing epidermal growth factor receptor activity. We propose the use of labeled NTS/NTSR1 complexes to enlarge the population eligible for therapy targeting HERs tyrosine kinase inhibitor or HER2 overexpression.


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