Cyclin E, A Potential Prognostic Marker in Breast Cancer

摘要

Cyclin E, a G1 cyclin essential for S phase entry with a profound role in oncogenesis, is overexpressed and present in lower molecular weight (LMW) isoforms in breast cancer cells and tumor tissues. Alteration and overexpression of cyclin E are linked to poor patient outcome. We have established the use of cyclin E as a prognostic marker for breast cancer. Tumor specimens from 400 breast cancer patients were examined; changes of cyclin E expression were compared with seven other established tumor markers to patient outcome. Altered expression of cyclin E was observed in 91% of all breast cancers with poor prognosis where patients either died of breast cancer or were still with cancer at the last contact date. Similarly in 93% of all breast cancer patients where cyclin E was either not altered, or its alteration was minimal, patients had a favorable prognosis. We have also deciphered the mechanism of deregulation of cyclin E in breast cancer cells giving rise to the LMW forms of cyclin E. Our studies show that the LMW forms of cyclin F detected at a much higher level in tumor cells, arise from post-translational action of a protease. We have been able to generate and knock out the tumor specific LMW pattern of cyclin E by transient transfection of FLAG-tagged cyclin E constant harboring these mutations in a breast cancer cell line. We have identified a novel elastase-type consensus sequence in the amino-terminus of cyclin E responsible for generating these tumor specific LMW isoforms. Lastly, studies using the drug Lovastatin demonstrated that this highly prescribed drug used to lower cholesterol levels is also capable of inducing all four cyclin dependent kinase inhibitors (CKIs) in a cell specific manner via cell cycle independent mechanism, through the inhibition of the proteasome. We have also devised a novel treatment strategy that protects normal cells against the toxic effects of chemotherapeutic agents.