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

摘要: // Sandra Dupouy 1 , * Van Kien Doan Zherui Wu 2 Najat Mourra 3 Jin Liu Olivier De Wever 4 Frederique Penault Llorca 5 Anne Cayre Amal Kouchkar 6 Gompel 7 Patricia Forgez UMRS U938, Hopital Saint-Antoine, Paris, France 1007 Universite Paris Descartes 45, Pathology Department The Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium Department, Jean Perrin Center, Clermont Ferrand, Alger Pierre and Marie Curie Algeria Gynecology Unit, Descartes, APHP, Hopitaux Universitaires Cochin Hotel-Dieu Broca, SD, VKD, ZW contributed equally to this work. Correspondence to: Forgez, e-mail: Patricia.forgez@inserm.fr Keywords: Cancer growth metastasis, neurotensin, EGFR, HER2, HER3, EGF like ligands Received: Novermber 28, 2013      Accepted: May 7, 2014      Published: October 03, 2014 ABSTRACT A present challenge in breast oncology research is identify therapeutical targets which could impact tumor progression. Neurotensin (NTS) its high affinity receptor (NTSR1) are up regulated 20% cancers, NTSR1 overexpression was shown predict a poor prognosis for year overall survival invasive carcinomas. Interactions between NTS induce pro-oncogenic biological effects associated with neoplastic processes Here, we depict the cellular mechanisms activated by NTS, contributing cancer cell aggressiveness. We show that neurotensin contribute enhancement experimental metastasis emergence an mice model. This effect ensued following HER3 over-expression autocrine activation increase metalloproteinase MMP9, HB-EGF Neuregulin culture media. EGFR over expression more intense response on migration invasion. Accordingly, lapatinib, EGFR/HER2 tyrosine kinase inhibitor, as well metformin, reduced cells overexpressing NTSR1. All effects, such adherence, migration, invasion, altered NTS/NTSR1 were abolished specific antagonist. strong statistical correlation NTS-NTSR1-and (p< 0.0001) HER3- HER2 0.001) found human tumors. Expression tumoral creates context aggressiveness enhancing epidermal factor activity. propose use labeled complexes enlarge population eligible therapy targeting HERs inhibitor or overexpression.