Cyclin E dysregulation and chromosomal instability in endometrial cancer.
Deregulation of cyclin E, an activator of cyclin-dependent kinase 2 (Cdk2), has been associated with a broad spectrum of human malignancies. Yet the mechanism linking abnormal cyclin E expression to carcinogenesis is largely unknown. The gene encoding the F-box protein hCdc4, a key component of the molecular machinery that targets cyclin E for degradation, is frequently mutated in endometrial cancer, leading to deregulation of cyclin E expression. Here we show that hCDC4 gene mutation and hyperphosphorylation of cyclin E, a parameter that usually correlates with hCDC4 mutation, have a strong statistically significant association with polypoidy and aneuploidy in endometrial cancer. On the contrary, elevated expression of cyclin E by itself was not significantly correlated with polyploidy or aneuploidy when tumors of similar grade are evaluated. These data suggest that impairment of cell cycle regulated proteolysis of cyclin E may be linked to carcinogenesis by promoting genomic instability.
Hubalek
Michael M
MM
Department of Obstetrics and Gynecology, Innsbruck University Hospital, Anichstrasse 35, A-6020 Innsbruck, Austria.
Widschwendter
Andreas
A
Erdel
Martin
M
Gschwendtner
Andreas
A
Fiegl
Heidi M
HM
Müller
Hannes M
HM
Goebel
Georg
G
Mueller-Holzner
Elisabeth
E
Marth
Christian
C
Spruck
Charles H
CH
Reed
Steven I
SI
Widschwendter
Martin
M
D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D043171:Chromosomal Instability / Q000235:genetics / Q000502:physiology*; D019927:Cyclin E / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence
D019927:Cyclin E