Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in high-grade liposarcoma

Cancer Res. 2013 Feb 15;73(4):1298-307. doi: 10.1158/0008-5472.CAN-12-2086. Epub 2013 Feb 7.

Abstract

Fibroblast growth factor (FGF) receptor (FGFR) substrate 2 (FRS2) is an adaptor protein that plays a critical role in FGFR signaling. FRS2 is located on chromosome 12q13-15 that is frequently amplified in liposarcomas. The significance of FRS2 and FGFR signaling in high-grade liposarcomas is unknown. Herein, we first comparatively examined the amplification and expression of FRS2 with CDK4 and MDM2 in dedifferentiated liposarcoma (DDLS) and undifferentiated high-grade pleomorphic sarcoma (UHGPS). Amplification and expression of the three genes were identified in 90% to 100% (9-11 of 11) of DDLS, whereas that of FRS2, CDK4, and MDM2 were observed in 55% (41 of 75), 48% (36 of 75), and 44% (33/75) of clinically diagnosed UHGPS, suggesting that these "UHGPS" may represent DDLS despite lacking histologic evidence of lipoblasts. Immunohistochemical analysis of phosphorylated FRS2 protein indicated that the FGFR/FRS2 signaling axis was generally activated in about 75% of FRS2-positive high-grade liposarcomas. Moreover, we found that FRS2 and FGFRs proteins are highly expressed and functional in three high-grade liposarcoma cell lines: FU-DDLS-1, LiSa-2, and SW872. Importantly, the FGFR selective inhibitor NVP-BGJ-398 significantly inhibited the growth of FU-DDLS-1 and LiSa-2 cells with a concomitant suppression of FGFR signal transduction. Attenuation of FRS2 protein in FU-DDLS-1 and LiSa-2 cell lines decreased the phosphorylated extracellular signal-regulated kinase 1/2 and AKT and repressed cell proliferation. These findings indicate that analysis of FRS2 in combination with CDK4 and MDM2 will more accurately characterize pathologic features of high-grade liposarcomas. Activated FGFR/FRS2 signaling may play a functional role in the development of high-grade liposarcomas, therefore, serve as a potential therapeutic target.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Arginine / analogs & derivatives
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Liposarcoma / genetics*
  • Liposarcoma / metabolism
  • Liposarcoma / pathology
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Middle Aged
  • Neoplasm Grading
  • Phenylurea Compounds / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Pyrimidines / pharmacology
  • RNA Interference
  • Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 4 / genetics
  • Receptor, Fibroblast Growth Factor, Type 4 / metabolism
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors
  • Receptors, Fibroblast Growth Factor / genetics*
  • Receptors, Fibroblast Growth Factor / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*

Substances

  • Adaptor Proteins, Signal Transducing
  • FRS2 protein, human
  • Membrane Proteins
  • Phenylurea Compounds
  • Pyrimidines
  • Receptors, Fibroblast Growth Factor
  • N,N-dimethylarginine
  • Arginine
  • infigratinib
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • FGFR2 protein, human
  • FGFR3 protein, human
  • FGFR4 protein, human
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptor, Fibroblast Growth Factor, Type 4
  • Proto-Oncogene Proteins c-akt
  • Cyclin-Dependent Kinase 4
  • Extracellular Signal-Regulated MAP Kinases