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Mol Oncol. 2015 Jan;9(1):282-94. doi: 10.1016/j.molonc.2014.08.012. Epub 2014 Sep 6.

Additive impact of HER2-/PTK6-RNAi on interactions with HER3 or IGF-1R leads to reduced breast cancer progression in vivo.

Author information

1
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.
2
Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany. Electronic address: natasa.anastasov@helmholtz-muenchen.de.
3
Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany. Electronic address: ines.hoefig@helmholtz-muenchen.de.
4
Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany. Electronic address: ksenbash@yandex.ru.
5
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.
6
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.
7
Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany. Electronic address: rosemann@helmholtz-muenchen.de.
8
Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany. Electronic address: aubele@helmholtz-muenchen.de.

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.

KEYWORDS:

Brk; Combined; ErbB2; PLA; Proximity ligation assay; RNA interference

PMID:
25241146
PMCID:
PMC5528674
DOI:
10.1016/j.molonc.2014.08.012
[Indexed for MEDLINE]
Free PMC Article

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