Cell Cycle and Cervical Carcinoma study.29-32 Almost all research data suggests that cyclin D1 expression is not found to correlate sig- nificantly with clinicopathological factors (histolo- gical type, tumor grade and stage, patient's age).33,34 Conversely, despite an underexpression of cyclin D1 in cervical carcinomas compared to normal cervical epithelium, positive immuno- staining, which was found in 28-32% of invasive carcinoma samples, was significantly associated with poor disease-free and overall survival.29,34 The latter report is the only one showing cyclin D1 gene amplification in cervical carcinomas (24%), but this was not correlated with overex- pression. Contradicting results have been reported about overexpression of cyclin D1 in immunostaining studies of cervical carcinoma. One study showed overexpression of cyclin D1 in 3% of patients, while underexpression was reported in another study.31,33 No significant increase in cyclin D1 protein levels, despite overexpression of cyclin D1 mRNA demonstrated by in situ hybridization, was reported in cervical carcinoma.28,29 These dis- crepancy might be attributed to the use of differ- ent antibodies, different scoring criteria for the detection assay, and the varying tumor tissue characteristics in different studies. In addition, some studies showed that the level of cyclin D1 was significantly lower in CIN and SCC compared with normal epithelium and that these levels correlated significantly with HPV positivity.28,33 Also, there is a low prevalence of G1 cyclins in cell lines with a mutated Rb gene, and DNA tumor virus infection can supplant tumor cell re- quirements for cyclin D1 protein. Cyclin D1 levels are reported as significantly lower in HPV-positive LSIL, HSIL, invasive SCC, or AC compared to HPV-negative cases and nor- mal cervical epithelium.28,30,35 Cyclin D1 and HPV E7 possess similar binding regions for pRb and pRb-related pocket proteins, and inactivation of pRb either by the cyclin/CDK complexes in G1 or by interaction with the high-risk HPV oncoprotein E7 may result in a decreased expression of cyclin D1 (Table 2). CDK4 The D-type cyclins (D1, D2, and D3) and their catalytic partners CDK4 and CDK6 act early in the G1 phase of the cell cycle.3 Mitogen-induced sig- nal transduction pathways promote the activation of cyclin D/CDK complexes at many levels, in- cluding gene transcription, cyclin D translation and stability, assembly of D cyclins with their CDK partners, and import of the holoenzymes into the nucleus, where they ultimately phos- Table 2. Expression Status of Cyclin D1 in Squamous Cervical Carcinoma Reference No. 28. Cho et al. 29. Bae et al. 30. Southern et al. 31. Nichols et al. 32. Kurzrock et al. 33. Skomedal et al. 34. Cheung et al. *Kim et al. Pathology CIN SCC CINIII SCC LSIL LSIL HSIL SCC SCC cell line SCC SCC SCC No. of cases Expression status 22 CI 0.87% underexpression 39 CI 5.88% underexpression 31 3% underexpression 32 28% underexpression 26 (LR HPV) 92% overexpression 29 (HR HPV) 87% overexpression 5 60% overexpression 8 12.5% underexpression 18 77.8% overexpression 10 No expression 74 3% underexpression 60 32% overexpressiom 41 Not different Technique Immuno-staining Immuno-staining Immuno-staining Southern blot/SSCP Immuno-staining Northern blot Immuno-staining Immuno-staining RT-PCR/ Western blot CIN, cervical intraepithelial neoplasia; SCC, squamous cell carcinoma; LSIL, low-grade squamous intraepithelial; HSIL, high- grade squamous intraepithelial; LR HPV, low risk HPV; HR HPV, high risk HPV; CI, cyclin index; RT-PCR, real-time polymerase chain reaction. a not published. *Authors of this review. Yonsei Med J Vol. 46, No. 5, 2005