Cyclin E and Cancer
Over-expression of cyclin E correlates with tumorigenesis. It is involved in various types of cancers, including breast, colon, bladder, skin and lung cancer. Besides that, dysregulated cyclin E activity causes cell lineage-specific abnormalities, such as impaired maturation due to increased cell proliferation and apoptosis or senescence.
Several mechanisms lead to the deregulated expression of cyclin E. In most cases, gene amplification causes the overexpression. Proteosome caused defected degradation is another mechanism. Loss-of-function mutations of FBXW7 were found in several cancer cells. FBXW7 encodes F-box proteins which target cyclin E for ubiquitination. Cyclin E overexpression can lead to G1 shortening, decrease in cell size or loss of serum requirement for proliferation.
Dysregulation of cyclin E occurs in 18-22% of the breast cancers. Cyclin E is a prognostic marker in breast cancer, its altered expression increased with the increasing stage and grade of the tumor. Low molecular weight cyclin E isoforms have been shown to be of great pathogenetic and prognostic importance for breast cancer. These isoforms are resistant to CKIs, bind with CDK2 more efficiently and can stimulate the cell cycle progression more efficiently. They are proved to be a remarkable marker of the prognosis of early-stage-node negative breast cancer. Importantly, a recent research pointed out cyclin E overexpression is a mechanism of Trastuzumab resistance in HER2+ breast cancer patients. Thus, co-treatment of trastuzumab with CDK2 inhibitors may be a valid strategy.
Cyclin E overexpression is implicated in carcinomas at various sites along the gastrointestinal tract. Among these carcinomas, cyclin E appears to be more important in stomach and colon cancer. Cyclin E overexpression was found in 50-60% of gastric adenomas and adenocarcinomas. In ~10% of colorectal carcinomas, cyclin E gene amplification is found, sometimes together with CDK2 gene amplification.
Cyclin E is also a useful prognostic marker for lung cancer. There is significant association between cyclin E over-expression and the prognosis of lung cancer. It is believed increased expression of cyclin E correlated with poorer prognosis.
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