ErbB2-driven breast cancer cell invasion depends on a complex signaling network activating myeloid zinc finger-1-dependent cathepsin B expression

Bo Rafn, Christian Friberg Nielsen, Sofie Hagel Andersen, Piotr Szyniarowski, Elisabeth Corcelle-Termeau, Erkka Valo, Nicole Fehrenbacher, Charlotta Johanne Olsen, Mads Daugaard, Christina Egebjerg, Trine Bøttzauw, Pekka Kohonen, Jesper Nylandsted, Sampsa Hautaniemi, José Moreira, Marja Jäättelä (Corresponding Author), Tuula Kallunki (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

74 Citations (Scopus)

Abstract

Aberrant ErbB2 receptor tyrosine kinase activation in breast cancer is strongly linked to an invasive disease. The molecular basis of ErbB2-driven invasion is largely unknown. We show that cysteine cathepsins B and L are elevated in ErbB2 positive primary human breast cancer and function as effectors of ErbB2-induced invasion in vitro. We identify Cdc42-binding protein kinase beta, extracellular regulated kinase 2, p21-activated protein kinase 4, and protein kinase C alpha as essential mediators of ErbB2-induced cysteine cathepsin expression and breast cancer cell invasiveness. The identified signaling network activates the transcription of cathepsin B gene (CTSB) via myeloid zinc finger-1 transcription factor that binds to an ErbB2-responsive enhancer element in the first intron of CTSB. This work provides a model system for ErbB2-induced breast cancer cell invasiveness, reveals a signaling network that is crucial for invasion in vitro, and defines a specific role and targets for the identified serine-threonine kinases.

Original languageEnglish
Pages (from-to)764-776
JournalMolecular Cell
Volume45
Issue number6
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

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    Rafn, B., Nielsen, C. F., Andersen, S. H., Szyniarowski, P., Corcelle-Termeau, E., Valo, E., Fehrenbacher, N., Olsen, C. J., Daugaard, M., Egebjerg, C., Bøttzauw, T., Kohonen, P., Nylandsted, J., Hautaniemi, S., Moreira, J., Jäättelä, M., & Kallunki, T. (2012). ErbB2-driven breast cancer cell invasion depends on a complex signaling network activating myeloid zinc finger-1-dependent cathepsin B expression. Molecular Cell, 45(6), 764-776. https://doi.org/10.1016/j.molcel.2012.01.029