The Role of the Low Molecular Weight (LMW) Isoforms of Cyclin E in Breast Cancer Tumorigenesis

Abstract

Abstract : Cyclin E is a positive regulator of the G1 to S phase transition of the cell cycle. In complex with CDK2 it is responsible for cells passing the restriction point. committing the cell to a round of the cell cycle progression. Previously this laboratory found that cyclin E is overexpressed and present in lower molecular weight (LMW) isoforms in breast cancer cells and tumor tissues compared to normal cells and tissues. To investigate the role of the LMW forms of cyclin E in tumorigenesis we are developing a model system of non-tumorigenic breast cells overexpressing the individual isoforms of cyclin E. Using this model system we aim to examine the role of the LMW forms in the process of transformation of normal cells in to neoplastic cells. We show that the LMW forms of cyclin E have higher kinase activity than the full length cyclin E. This activity is due to increased efficiency of binding of the LMW forms to the kinase subunit, CDK2, along with increased resistance to the inhibitors 21 and p27 compared to the full length cyclin E. Therefore, the LMW forms of cyclin E could play an important role in the pathogenesis of breast cancer.