title: ErbB2-driven breast cancer cell invasion depends on a complex signaling network activating myeloid zinc finger-1-dependent cathepsin B expression.
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.
authors.affiliation: Unit of Cell Death and Metabolism and Centre for Genotoxic Stress Research, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen 2100, Denmark.
authors.forename: Bo
authors.initials: B
authors.lastname: Rafn
authors.forename: Christian Friberg
authors.initials: CF
authors.lastname: Nielsen
authors.forename: Sofie Hagel
authors.initials: SH
authors.lastname: Andersen
authors.forename: Piotr
authors.initials: P
authors.lastname: Szyniarowski
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Corcelle-Termeau
authors.forename: Erkka
authors.initials: E
authors.lastname: Valo
authors.forename: Nicole
authors.initials: N
authors.lastname: Fehrenbacher
authors.forename: Charlotta Johanne
authors.initials: CJ
authors.lastname: Olsen
authors.forename: Mads
authors.initials: M
authors.lastname: Daugaard
authors.forename: Christina
authors.initials: C
authors.lastname: Egebjerg
authors.forename: Trine
authors.initials: T
authors.lastname: Bøttzauw
authors.forename: Pekka
authors.initials: P
authors.lastname: Kohonen
authors.forename: Jesper
authors.initials: J
authors.lastname: Nylandsted
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: José
authors.initials: J
authors.lastname: Moreira
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
authors.forename: Tuula
authors.initials: T
authors.lastname: Kallunki
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002401:Cathepsin B / Q000235:genetics* / Q000378:metabolism*; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D065636:Myotonin-Protein Kinase; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D002401:Cathepsin B; D056668:Cathepsin L; D051741:Kruppel-Like Transcription Factors; D019950:Mitogen-Activated Protein Kinase 1; D065636:Myotonin-Protein Kinase; D051571:Protein Kinase C-alpha; D011505:Protein-Tyrosine Kinases; D050784:Proto-Oncogene Protein c-ets-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D054462:p21-Activated Kinases; C494041:ETS1 protein, human; C085969:MZF1 protein, human; C118666:CDC42BPB protein, human; C116367:PAK4 protein, human; C508053:ERBB2 protein, human; C535150:MAPK1 protein, human; C533912:CTSB protein, human; C534281:CTSL protein, human