Mechanisms of Cyclin E Deregulation in Cancer

The first report of cyclin E gene amplification as tumor-linked mechanism for elevation of cyclin E expression was based on a breast cancer (BC) derived cell line (15). Subsequently cyclin E gene amplification has been reported at varying frequencies in a variety of different tumor types, particularly gastrointestinal and ovarian cancer (16-18). In BC, however, cyclin E gene amplification is rare (16). We therefore sought to determine if deregulation of cyclin E could be mediated by defects in the cyclin E degradation pathway. First, we analyzed tumor-derived DNA for mutations in cyclin E itself that might impair phosphorylation-dependent ubiquitination. Single stranded conformational polymorphism (SSCP) analysis of DNA from more than 100 tumors yielded no mutations that could account for cyclin E stabilization. Therefore, we turned to analysis of the cyclin E ubiquitation machinery. SCF protein-ubiquitin ligases are characterized by specificity factors, known as F-box proteins that target specific sub-groups of proteins (19, 20). We analyzed the F-box protein that targets cyclin E, hCdc4 (13,21,22) for mutations in tumor-derived cell lines and in primary tumors. One out of 8 BC-derived cell lines tested was found to have mutated hCDC4 and loss of heterozygosity (LOH) (13). This correlated with stable cyclin E. Next, primary ovarian and endometrial tumors were analyzed by SSCP for hCDC4 mutation. Whereas 0/40 ovarian tumors had mutations in hCDC4 based on SSCP analysis, mutations were found in 16% (8/51) of endometrial tumors (23). Where appropriate linked markers were available, LOH could be demonstrated in the hCDC4-mutated tumors. These data strongly suggest that hCdc4 is a classical tumor suppressor. Consistent with this, hCDC4 maps to chromosomal region 4q32, a site of frequent allelic loss in a broad spectrum of human cancers. Finally, hCDC4 mutation status may have prognostic value. Of the endometrial tumors analyzed, hCDC4 mutation correlated with higher grade, more advanced stage, and metastasis (23). The latter parameter is significant, since metastasis is not frequent in endometrial cancer.

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