title: Brain-derived neurotrophic factor and neurotrophin-4/5 are expressed in breast cancer and can be targeted to inhibit tumor cell survival.
abstract: OBJECTIVE
  Given that nerve growth factor has previously been shown to be involved in breast cancer progression, we have tested here the hypothesis that the other neurotrophins (NT) are expressed and have an influence in breast tumor growth.
  
  
  METHODS
  The expression of brain-derived neurotrophic factor (BDNF), NT-3 and NT-4/5, as well as the neurotrophin receptor p75(NTR), TrkB, and TrkC, was studied by RT-PCR, Western blotting, and immunohistochemistry in cell lines and tumor biopsies. The biological impacts of neurotrophins, and associated mechanisms, were analyzed in cell cultures and xenografted mice.
  
  
  RESULTS
  BDNF and NT-4/5 were expressed and secreted by breast cancer cells, and the use of blocking antibodies suggested an autocrine loop mediating cell resistance to apoptosis. The corresponding tyrosine kinase receptor TrkB was only rarely observed at full length, whereas the expression of TrkB-T1, lacking the kinase domain, as well as p75(NTR), were detected in all tested breast cancer cell lines and tumor biopsies. In contrast, NT-3 and TrkC were not detected. SiRNA against p75(NTR) and TrkB-T1 abolished the antiapoptotic effect of BDNF and NT-4/5, whereas the pharmacological inhibitors K252a and PD98059 had no effect, suggesting the involvement of p75(NTR) and TrkB-T1, but not kinase activities from Trks and MAPK. In xenografted mice, anti-BDNF, anti-NT-4/5, anti-p75(NTR), or anti-TrkB-T1 treatments resulted in tumor growth inhibition, characterized by an increase in cell apoptosis, but with no change in proliferation.
  
  
  CONCLUSIONS
  BDNF and NT-4/5 contribute to breast cancer cell survival and can serve as prospective targets in attempts to inhibit tumor growth.
authors.affiliation: INSERM U 908 Growth factor signaling in breast cancer cells. Functional proteomics, IFR-147, University of Lille, Villeneuve d'Ascq, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Vanhecke
authors.forename: Eric
authors.initials: E
authors.lastname: Adriaenssens
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Verbeke
authors.forename: Samuel
authors.initials: S
authors.lastname: Meignan
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Germain
authors.forename: Nathalie
authors.initials: N
authors.lastname: Berteaux
authors.forename: Victor
authors.initials: V
authors.lastname: Nurcombe
authors.forename: Xuefen
authors.initials: X
authors.lastname: Le Bourhis
authors.forename: Hubert
authors.initials: H
authors.lastname: Hondermarck
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D019208:Brain-Derived Neurotrophic Factor / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000473:pathology; D018276:Carcinoma, Medullary / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D008207:Lymphatic Metastasis; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009414:Nerve Growth Factors / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D007155:Immunologic Factors; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D034741:RNA, Small Interfering; D020800:Receptor, Nerve Growth Factor; D020813:Receptor, trkB; D020812:Receptor, trkC; C073922:neurotrophin 4