Objective:We investigated the relationship between cyclin E mRNA overexpression and p53 protein accumulation in epithelial ovarian cancers.
Methods:mRNA was isolated and cDNA was prepared from 36 epithelial ovarian tumors (three adenomas, three low malignant potential tumors, and 30 carcinomas), and six normal ovaries. The cyclin E mRNA expression levels relative to an internal control, β-tubulin, were determined by semiquantitative polymerase chain reaction (PCR). Cyclin E and p53 protein expression in ovarian cancer tissues were examined by immunohistochemistry using the same series of samples. Fisher exact test of significance and an unpaired t test were used for statistical analysis.
Results:Considerable levels of cyclin E mRNA were detected in all normal ovaries and ovarian tumor samples examined by semiquantitative PCR amplification. mRNA levels of cyclin E were significantly higher in nine of 30 (30%) ovarian cancers compared with those in normal ovaries. The immunohistochemical expression of cyclin E protein was confirmed in the nuclei of tumor cells in 13 of 30 (43%) ovarian cancers. p53 protein accumulation was detected in 12 of 30 (40%) ovarian cancers examined. There was a significant inverse correlation between cyclin E mRNA overexpression and p53 protein accumulation (P <.01, Fisher exact test).
Conclusions:Cyclin E mRNA overexpression frequently occurs in ovarian cancers without p53 protein accumulation. Cyclin E might have an important effect on the development of a limited number of ovarian cancers.
1. Sherr CJ. G1 phase progression: Cycling on cue. Cell1994;79:551-555.
2.
2. Hunter T, Pines J. Cyclins and cancer. II. Cyclin D and CDK inhibitors come of age. Cell1994;79:573-582.
3.
3. Clurman B, Roberts JM. Cell cycle and cancer. J Natl Cancer Inst1995;87:1499-1501.
4.
4. Ohtsubo M, Theodoras AM, Schumacher J, Roberts J, Pagano M. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol1995;15:2612-2624.
5.
5. Mumberg D, Haas K, Moroy T, et al. Uncoupling of DNA replication and cell cycle progression by human cyclin E. Oncogene1996;13:2493-2497.
6.
6. Keyomarsi K, O'Leary N, Molnar G, Lees E, Fingert HJ, Pardee AB. Cyclin E, a potential prognostic marker for breast cancer. Cancer Res1994;54:380-385.
7.
7. Porter P, Malone K, Haegerty G, et al. Expression of cell-cycle regulators p27kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med1997;3:222-225.
8.
8. Kitahara K, Yasui W, Kuniyasu H, et al. Concurrent amplification of cyclin E and Cdk2 genes in colorectal carcinomas. Int J Cancer1995;62:25-28.
9.
9. Courjal F, Louason G, Speiser P, Katsaros D, Zeillinger R, Theillet C. Cyclin gene amplification and overexpression in breast and ovarian cancers: Evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors. Int J Cancer (Pred Oncol)1996;69:247-253.
10.
10. Marone M, Scambia G, Giannttelli C, et al. Analysis of cyclin E and Cdk2 in ovarian cancer: Gene amplification and RNA overexpression. Int J Cancer1998;75:34-39.
11.
11. Session DR, Lee GS, Choi J, Wolgemuth DJ. Expression of cyclin E in gynecologic malignancies. Gynecol Oncol1999;72:32-37.
12.
12. Kupryjanczyk J, Thor AD, Beauchamp R, et al. P53 gene mutation and protein accumulation in human ovarian cancer. Proc Natl Acad Sci U S A1993;90:4961-4965.
13.
13. Milner BJ, Allan LA, Eccles DM, et al. P53 mutation is a common genetic event in ovarian carcinoma. Cancer Res1993;53:2128-2132.
14.
14. Kohler MF, Marks JR, Wiseman RW, et al. Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer. J Natl Cancer Inst1993;85:1513-1519.
15.
15. Niwa K, Itoh M, Murase T, et al. Alteration of p53 gene in ovarian carcinoma: Clinicopathological correlation and prognostic significance. Br J Cancer1994;70:1191-1197.
16.
16. McManus DT, Yap EPH, Maxwell P, Russell SHE, Toner PG, McGee OD. p53 expression, mutation, and allelic deletion in ovarian cancer. J Pathol1994;174:159-168.
17.
17. Teneriello MG, Ebina M, Linnoila RI, et al. p53 and K-ras gene mutations in epithelial ovarian neoplasms. Cancer Res1993;53:3103-3108.
18.
18. Levine AJ, Perry ME, Chang A, et al. The role of the p53 tumor-suppressor gene in tumorigenesis. Br J Cancer1994;69:409-416.
19.
19. Rogel A, Popliker M, Webb CG, Oren M. p53 cellular tumor antigen: Analysis of mRNA levels in normal adult tissues, embryos and tumors. Mol Cell Biol1985;5:2851-2855.
20.
20. Finlay CA, Hinds PW, Tan TH, Eliyahu D, Oren M, Levine J. Activating mutations for transformation by p53 produce a gene product that forms a hsc70-p53 complex with an altered half life. Mol Cell Biol1988;8:531-539.
21.
21. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics. CA Cancer J Clin1996;46:5-27.
22.
22. Scully RE. Tumors of the ovary and maldeveloped gonads. 2nd series. Washington, DC: Armed Forces Institute of Pathology, 1979:53-151.
23.
23. Shigemasa K, Hu C, West CM, et al. p16 overexpression: A potential early indicator of transformation in ovarian carcinoma. J Soc Gynecol Invest1997;4:95-102.
24.
24. Shigemasa K, Hu C, West CM, et al. p21: A monitor of p53 dysfunction in ovarian neoplasia. Int J Gynecol Cancer1997;7:296-303.
25.
25. Shigemasa K, Tanimoto H, Parham GP, Parmley TH, Ohama K, O'Brien TJ. Cyclin D1 overexpression and p53 mutation status in epithelial ovarian cancer. J Soc Gynecol Investig1999;6:102-108.
26.
26. Clurman BE, Sheaff RJ, Thress K, Groudine M, Roberts JM. Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. Genes Dev1996;10:1979-1990.
27.
27. Lonardo F, Rusch V, Langenfeld J, Dmitrovsky E, Klimstra DS. Overexpression of cyclins D1 and E is frequent in bronchial preneoplasia and precedes squamous cell carcinoma development. Cancer Res1999;59:2470-2476.
28.
28. Siwicki JK, Hedberg Y, Nowak R, et al. Long-term cultured IL-2-dependent T cell lines demonstrate p16(INK4a) overexpression, normal pRb/p53, and unregulation of cyclins E or D2. Exp Gerontol2000;35:375-388.
