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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. Copyright © 2012 Elsevier Inc. All rights reserved.


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, Tuula Kallunki. ErbB2-driven breast cancer cell invasion depends on a complex signaling network activating myeloid zinc finger-1-dependent cathepsin B expression. Molecular cell. 2012 Mar 30;45(6):764-76

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PMID: 22464443

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