Constitutive activation of neuregulin/ERBB3 signaling pathway in clear cell sarcoma of soft tissue.
Clear cell sarcoma of soft tissue (CCSST) represents a highly malignant tumor of the musculoskeletal system that is characterized by the chromosomal translocation t(12;22)(q13;q12) of the Ewing sarcoma gene (EWSR1) and activating transcription factor 1 (ATF1). In a former microarray expression study, we identified ERBB3, a member of the epidermal growth factor receptor (EGFR) family, as a promising new diagnostic marker in the differential diagnosis of CCSST. Here we show that, besides ErbB3, all CCSST cell lines (n = 8) also express the ErbB2 receptor or the ErbB4 receptor, representing an adequate coreceptor of ErbB3. The phosphorylation status of ErbB3 revealed these receptor pairs to be either constitutively activated in CCSST cells with high neuregulin-1 (NRG1) expression (n = 4) or activatable by exogenic NRG1 in cells showing low amounts of NRG1 mRNA (n = 4). Exogenous NRG1 stimulated the growth of a subset of CCSST cells but did not affect the kinetics of another subset. This difference was not strictly dependent on endogenous NRG1 expression; however, the growth-inhibiting effect of the pan-ErbB tyrosine kinase inhibitor CI-1033 or PD158780 clearly correlated with NRG1 expression indicating an autocrine growth stimulation loop which may constitute an interesting target of new therapeutic strategies in this tumor entity.
Schaefer
Karl-Ludwig
KL
Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany.
Brachwitz
Kristin
K
Braun
Yvonne
Y
Diallo
Raihanatou
R
Wai
Daniel H
DH
Zahn
Susanne
S
Schneider
Dominik T
DT
Kuhnen
Cornelius
C
Vollmann
Arabel
A
Brockhoff
Gero
G
Gabbert
Helmut E
HE
Poremba
Christopher
C
D000483:Alleles; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D020890:Neuregulin-1 / Q000378:metabolism*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000737:chemistry; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D018227:Sarcoma, Clear Cell / Q000378:metabolism*; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000378:metabolism*
C107875:6-(methylamino)pyrido(3,4-d)pyrimidine; D020890:Neuregulin-1; D009841:Oligonucleotides; D011743:Pyrimidines; D020893:Receptor, ErbB-3