Introduction: Deregulation of cyclin E has been correlated with both grade and prognosis in a variety of epithelial tumors. In a breast cancer model, the most significant manifestation of cyclin E deregulation is the generation of low molecular weight (LMW) isoforms which are hyperactive and correlate with both poor prognosis and genomic instability. The significance of cyclin E deregulation in mesenchymal soft tissue sarcomas (STS) remains undetermined. In this study, we evaluated various STS cell lines and tumor specimens for the presence of the LMW forms of cyclin E and their relationship with cdk2 and p27. Methods: Western blot analysis was used to assess differences in protein expression. Immunoprecipitation assays were performed to determine protein-protein interactions. Results: Western blot analysis demonstrated that the LMW forms of cyclin E were present in 4 different STS cell lines (HT1080, SKLMS-1, SW982, and SW872), as well as in 3 different STS tissue specimens (gastrointestinal stromal tumor, leiomyosarcoma, and liposarcoma) but not in mesenchymal cells or normal small intestine. Immunoprecipitation studies demonstrated that CDK2 and p27 bind to both full-length cyclin E as well as the LMW forms. In addition, our results show that these LMW forms of cyclin E are hyperactive in STS cells and tumor tissue samples and are resistant to inhibition by p27. Conclusions: We found that the LMW forms of cyclin E are present in STS cells and tumor tissue samples. CDK2 and p27 form protein complexes with both the full-length and LMW forms of cyclin E with increased kinase activity but show resistance to inhibition by p27. Our results suggest that the LMW forms of cyclin E are promising biomarkers for high grade STS and may be novel targets for tumor-targeted therapy for this disease.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]