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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / therapy
  • Cell Line, Tumor
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • RNA Interference*
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Receptor, ErbB-3 / genetics
  • Receptor, ErbB-3 / metabolism*
  • Receptor, IGF Type 1
  • Receptors, Somatomedin / genetics
  • Receptors, Somatomedin / metabolism*
  • Xenograft Model Antitumor Assays


  • IGF1R protein, human
  • Neoplasm Proteins
  • Receptors, Somatomedin
  • ERBB2 protein, human
  • ERBB3 protein, human
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Receptor, IGF Type 1
  • PTK6 protein, human