Journal
MOLECULAR CELL
Volume 45, Issue 6, Pages 764-776Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2012.01.029
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Funding
- Danish Cancer Society
- Danish Medical Research Council
- APO-SYS (EU)
- Danish National Research Foundation
- Meyer Foundation
- M.L. Jorgensen and Gunnar Hansens Foundation
- Novo Nordisk Foundation
- Danish Cancer Research Foundation
- Alfred Benzon Foundation
- Vilhelm Pedersen Foundation
- A Race Against Breast Cancer Foundation
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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.
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