title: Activation of EGFR, HER2 and HER3 by neurotensin/neurotensin receptor 1 renders breast tumors aggressive yet highly responsive to lapatinib and metformin in mice.
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.
authors.affiliation: UMRS U938, Hôpital Saint-Antoine, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Dupouy
authors.affiliation: UMRS U938, Hôpital Saint-Antoine, Paris, France.
authors.forename: Van Kien
authors.initials: VK
authors.lastname: Doan
authors.affiliation: UMRS U938, Hôpital Saint-Antoine, Paris, France. UMRS 1007, Université Paris Descartes 45, Paris, France.
authors.forename: Zherui
authors.initials: Z
authors.lastname: Wu
authors.affiliation: UMRS U938, Hôpital Saint-Antoine, Paris, France. Pathology Department Hôpital Saint-Antoine, Paris, France.
authors.forename: Najat
authors.initials: N
authors.lastname: Mourra
authors.affiliation: UMRS 1007, Université Paris Descartes 45, Paris, France.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: The Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
authors.affiliation: Pathology Department, Jean Perrin center, Clermont Ferrand, France.
authors.forename: Frédérique Penault
authors.initials: FP
authors.lastname: Llorca
authors.affiliation: Pathology Department, Jean Perrin center, Clermont Ferrand, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Cayre
authors.affiliation: Pathology Department, Alger Pierre and Marie Curie center, Algeria.
authors.forename: Amal
authors.initials: A
authors.lastname: Kouchkar
authors.affiliation: UMRS 1007, Université Paris Descartes 45, Paris, France. Gynecology Unit, Université Paris Descartes, APHP, Hôpitaux Universitaires Cochin Hôtel-Dieu Broca, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Gompel
authors.affiliation: UMRS 1007, Université Paris Descartes 45, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Forgez
mesh_terms: D000328:Adult; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D000077341:Lapatinib; D061986:MCF-7 Cells; D008687:Metformin / Q000008:administration & dosage; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009496:Neurotensin / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000008:administration & dosage; D020239:Receptor Cross-Talk; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D018028:Receptors, Neurotensin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D066246:ErbB Receptors; D000077341:Lapatinib; D008687:Metformin; D009496:Neurotensin; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human