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; Tuula Kallunki

doi:10.1016/j.molcel.2012.01.029

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

Mol Cell. 2012 Mar 30;45(6):764-76. doi: 10.1016/j.molcel.2012.01.029.

Authors

Bo Rafn¹, 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

Affiliation

¹ Unit of Cell Death and Metabolism and Centre for Genotoxic Stress Research, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen 2100, Denmark.

PMID: 22464443
DOI: 10.1016/j.molcel.2012.01.029

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Breast Neoplasms / pathology*
Cathepsin B / genetics*
Cathepsin B / metabolism*
Cathepsin L / genetics
Cathepsin L / metabolism
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Humans
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism*
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / metabolism
Myotonin-Protein Kinase
Neoplasm Invasiveness
Promoter Regions, Genetic
Protein Kinase C-alpha / genetics
Protein Kinase C-alpha / metabolism
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism
Proto-Oncogene Protein c-ets-1 / genetics
Proto-Oncogene Protein c-ets-1 / metabolism
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism*
Response Elements
Signal Transduction
p21-Activated Kinases / genetics
p21-Activated Kinases / metabolism

Substances

ETS1 protein, human
Kruppel-Like Transcription Factors
MZF1 protein, human
Proto-Oncogene Protein c-ets-1
CDC42BPB protein, human
PAK4 protein, human
ERBB2 protein, human
Protein-Tyrosine Kinases
Receptor, ErbB-2
Myotonin-Protein Kinase
p21-Activated Kinases
Protein Kinase C-alpha
MAPK1 protein, human
Mitogen-Activated Protein Kinase 1
CTSB protein, human
Cathepsin B
CTSL protein, human
Cathepsin L