title: Additive impact of HER2-/PTK6-RNAi on interactions with HER3 or IGF-1R leads to reduced breast cancer progression in vivo.
abstract: The human epidermal growth factor receptor 2 (HER2) and the protein tyrosine kinase 6 (PTK6) are often co- and over-expressed in invasive breast cancers. At early diagnosis, only distinct groups, such as HER2-or hormone receptor-positive benefit from a targeted therapy. However, a part of these tumours develops resistance within a year of administration of the drug but the majority of the patients depends on general therapies with severe side effects. A PTK6-directed approach does not yet exist. In our present study, we successfully demonstrate, in vitro and in vivo, a significantly additive reduction of tumourigenesis of breast cancer cells simultaneously depleted of both HER2 and PTK6. In comparison with single RNAi approaches, the combined RNAi (co-RNAi) led to a stronger reduced phosphorylation of tumour-promoting proteins. Moreover, the co-RNAi additively decreased cell migration as well as two and three dimensional cell proliferation in vitro. The in vivo experiments showed an additive reduction (p < 0.00001) in the growth of xenografts due to the co-RNAi compared with HER2 or PTK6 RNAi alone. Interestingly, the complexes of HER2 or PTK6 with tumour-relevant interaction partners, such as HER3 or the insulin-like growth factor receptor 1 (IGF-1R), respectively, were also reduced in xenografts although their protein expression levels were not affected following the co-RNAi of HER2 and PTK6. Our present study reveals the potential of using combined HER2- and PTK6- knockdown as a powerful strategy for the treatment of breast cancers. Therefore, the combined inhibition of these proteins may represent an attractive tool for efficient therapy of breast cancers.
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany. Electronic address: natalie.falkenberg@helmholtz-muenchen.de.
authors.forename: Natalie
authors.initials: N
authors.lastname: Falkenberg
authors.affiliation: Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany. Electronic address: natasa.anastasov@helmholtz-muenchen.de.
authors.forename: Nataša
authors.initials: N
authors.lastname: Anastasov
authors.affiliation: Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany. Electronic address: ines.hoefig@helmholtz-muenchen.de.
authors.forename: Ines
authors.initials: I
authors.lastname: Höfig
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany. Electronic address: ksenbash@yandex.ru.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Bashkueva
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany. Electronic address: katrin.lindner@helmholtz-muenchen.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Lindner
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany; Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany. Electronic address: hoefler@lrz.tum.de.
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.affiliation: Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany. Electronic address: rosemann@helmholtz-muenchen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Rosemann
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany. Electronic address: aubele@helmholtz-muenchen.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aubele
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; C000597236:IGF1R protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C088375:PTK6 protein, human
keywords: Brk; Combined; ErbB2; PLA; Proximity ligation assay; RNA interference