Summary
The expression of cyclin D1 protein in tumour sections from 81 patients with epithelial ovarian cancer was analysed using immunohistochemistry. The tumours that overexpressed cyclin D1 in more than 10% of neoplastic cells were considered positive. Thus overexpression of cyclin D1 was observed in 72/81 (89%) of the cases examined. Protein was detected in both the nucleus and the cytoplasm in 24/81 (30%) and localized exclusively in the cytoplasm in 48/81 (59%) of the tumours. Cyclin D1 was overexpressed in both borderline and invasive tumours. There was no association between protein overexpression and tumour stage and differentiation. Furthermore, no correlation between cyclin D1 expression and clinical outcome was observed. However, in tumours overexpressing cyclin D1 (n = 72), the proportion displaying exclusively cytoplasmic localization of protein was higher in those with serous compared with non-serous histology (P = 0.004, odds ratio 4.8, 95% confidence interval 1.4–19.1). Western analysis using a monoclonal antibody to cyclin D1 identified a 36 kDa protein in homogenates from seven tumours displaying cytoplasmic only and one tumour demonstrating both nuclear and cytoplasmic immunostaining. Using restriction fragment length polymorphism polymerase chain reaction and PCR-multiplex analysis, amplification of the cyclin D1 gene (CCNDI) was detected in 1/29 of the tumours demonstrating overexpression of cyclin D1 protein. We conclude that deregulation of CCND1 expression leading to both cytoplasmic and nuclear protein localization is a frequent event in ovarian cancer and occurs mainly in the absence of gene amplification.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Barbieri, F, Cagnoli, M, Ragni, N, Pedulla, F, Foglia, G & Alama, A (1997). Expression of cyclin D1 correlates with malignancy in human ovarian tumours. Br J Cancer 75: 1263–1268.
Bellacosa, A, Almadori, G, Cavallo, S, Cadoni, G, Galli, J, Ferrandina, G, Scambia, G & Neri, G (1996). Cyclin D1 gene amplification in human laryngeal squamous cell carcinomas: prognostic significance and clinical implications. Clin Cancer Res 2: 175–180.
Betticher, DC, Heighway, J, Haselton, PS, Altermatt, HJ, Ryder, WDJ, Cerny, T & Thatcher, N (1996). Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. Br J Cancer 73: 294–300.
Betticher, DC, Thatcher, N, Altermatt, HJ, Hoban, P, Ryder, WDJ & Heighway, J (1995). Alternate splicing produces a novel cyclin D1 transcript. Oncogene 11: 1005–1011.
Bringuier, PP, Tamimi, YE, Schuuring, E & Schalken, J (1996). Expression of cyclin D1 and EMS1 in bladder tumours: relationship with chromosome 11q13 amplification. Oncogene 12: 1747–1753.
Callender, T, El-Naggar, AK, Lee, MS, Frankenthaler, R, Luna, MA & Batsakis, JG (1994). PRAD 1 (CCND1)/Cyclin D1 oncogene amplification in head and neck squamous cell carcinoma. Cancer 74: 152–158.
Chang, J, Bridgewater, J, Gore, M, Fischer, C, Schofield, J, A’Hern, R, Ponder, B, Jacobs, I, McKeage, M, Kelland, L & Harap, K (1994). Non surgical aspects of ovarian cancer. Lancet 343: 335–340.
Courjal, F, Louason, G, Speiser, P, Katsaros, D, Zeillinger, R & Theillet, C (1996). Cyclin gene amplification and overexpression in breast and ovarian cancers: evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumours. Int J Cancer 69: 247–253.
de Boer, CJ, Loyson, S, Kluin, PM, Kluin-Nelemans, HC, Schruuring, E & van Krieken, JH (1993). Multiple breakpoints with the bcl-1 locus in B-cell lymphoma: rearrangements of the cyclin D1 gene. Cancer Res 53: 4148–4152.
de Boer, CJ, Schuuring, E, Dreef, E, Peters, G, Bartek, J, Kluin, PM & van Krieken, JH (1995). Cyclin D1 protein analysis in the diagnosis of matel cell lymphoma. Blood 86: 2715–2723.
Dhar, KK, Branigan, K, Hand, P, Howells, R, Redman, C, Strange, R, Heighway, J & Hoban, P (1997). Analysis of Cyclin D1 amplification and overexpression in ovarian cancer. Acta Obstet Gynaecol Scand 76: 19
Diehl, JA & Sherr, CJ (1997). A dominant-negative mutant prevents nuclear import of cyclin dependent kinase 4 (CDK4) and its phosphorylation by CDK- activating kinase. Mol Cell Biol 17: 7362–7364.
Dulic, V, Drullinger, LF, Lees, E, Reed, SI & Stein, GH (1993). Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdk2 and cyclin D1-Cdk2 complexes. Proc Natl Acad Sci USA 90: 11034–11038.
Foulkes, WD, Campbell, IG, Stamp, G & Trowsdale, J (1993). Loss of heterozygosity and amplification on chromosome 11q in human ovarian cancer. Br J Cancer 67: 268–273.
Gabra, H, Watson, JEV, Taylor, KJ, Mackay, J, Leonard, RC, Steel, CM, Porteous, DJ & Smyth, JF (1996). Definition and refinement of loss of heterozygosity at 11q23.3–q24.3 in epithelial ovarian cancer associated with poor prognosis. Cancer Res 56: 950–954.
Gansauge, S, Gansauge, F, Ramadani, M, Stobbe, H, Rau, B, Harada, N & Beger, H (1997). Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res 57: 1634–1637.
Gillett, C, Fantl, V, Smith, R, Fisher, C, Bartek, J, Dickson, C, Barnes, D & Peters, G (1994). Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res 54: 1812–1817.
Gillett, C, Smith, P, Gregory, W, Richards, M, Millis, R, Peters, G & Barnes, D (1996). Cyclin D1 and prognosis in human breast cancer. Int J Cancer 69: 92–99.
Howells, REJ, Redman, CWE, Dhar, KK, Sarhanis, P, Musgrove, C, Jones, PW, Alldersea, J, Fryer, AA, Hoban, P & Strange, RC (1998). Association of glutathione S-transferase GSTM1 and GSTT1 null genotypes with clinical outcome in epithelial ovarian cancer. Clin Cancer Res 4: 2439–2445.
Hung, W-C, Chai, C-Y, Huang, J-S & Chuang, L-Y (1996). Expression of cyclin D1 and c-Ki-ras gene in human epithelial ovarian tumours. Hum Pathol 27: 1324–1328.
Kotelnikov, VM, Coon, JS, Mundle, S, Kelanic, S, LaFollette, S, Taylor, IVS, Hutchinson, J, Panje, W, Caldarelli, DD & Preisler, HD (1997). Cyclin D1 expression in squamous cell carcinomas of the head and neck and in oral mucosa in relation to proliferation and apoptosis. Clin Cancer Res 3: 95–101.
Kranenburg, O, van der Eb, AJ & Zantema, A (1996). Cyclin D1 is an essential mediator of apoptotic neuronal cell death. EMBO J 15: 46–54.
Kurzrock, R, Ku, S & Talpaz, M (1995). Abnormalities in the PRAD1 (Cyclin D1/ BCL-1) oncogene are frequent in cervical and vulval squamous cell carcinoma cell lines. Cancer 75: 584–590.
Kwon, TK, Buchholz, MA, Gabrielson, EW & Nordin, AA (1995). A novel cytoplasmic substrate for cdk4 and cdk6 in normal and malignant epithelial derived cells. Oncogene 11: 2077–2083.
La Baer, J, Garrett, MD, Stevenson, LF, Slingerland, JM, Sandhu, C, Chou, HS, Fattaey, A & Harlow, E (1997). New functional activities for the p21 family of CDK inhibitors. Genes Dev 11: 847–862.
Lukas, J, Bartkova, J, Welcker, M, Peterson, O, Peters, G, Strauss, M & Bartek, J (1995). Cyclin D2 is a moderately oscillating nucleoprotein required for G1 phase progression in specific cell types. Oncogene 10: 2125–2134.
Lucibello, FC, Sewing, A, Brusselbach, S, Burger, C & Muller, R (1993). Deregulation of cyclins D1 and E and suppression of cdk2 and cdk4 in senescent human fibroblasts. J Cell Sci 105: 123–133.
Masciullo, V, Scambia, G, Marone, M, Giannitelli, C, Ferrandina, G, Bellacosa, A, Bendetti Panici, P & Mancus, OS (1997). Altered expression of cyclin D1 and CDK4 genes in ovarian carcinomas. Int J Cancer 74: 390–395.
Michalides, R, van Veelen, N, Hart, A, Loftus, B, Wientjens, E & Balm, A (1995). Overexpression of cyclin D1 correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Cancer Res 55: 975–978.
Motokura, T, Bloom, T, Kim, HG, Juppner, H, Ruderman, JV, Kronenberg, HM & Arnold, A (1991). A novel cyclin encoded by a bcl-1 linked candidate oncogene. Nature 350: 512–515.
Musgrove, EA, Lee, CS, Buckley, MF & Sutherland, RL (1994). Cyclin D1 induction in breast cancer cells shorten G1 and is sufficient for cells arrested in G1 to complete the cell cycle. Proc Natl Acad Sci USA 91: 8022–8026.
Nakamura, S, Seto, M, Banno, S, Suzuki, S, Koshikawa, T, Kitoh, K, Kagami, Y, Ogura, M, Yatabe, Y, Kojima, M, Motoori, T, Takahashi, T, Ueda, R & Suchi, T (1994). Immunohistochemical analysis of cyclin D1 protein in hematopoietic neoplasms with special reference to mantel cell lymphoma. Jpn J Cancer Res 85: 1270–1279.
Nishida, N, Fukuda, Y, Komeda, T, Kita, R, Sando, T, Furukawa, M, Amenomori, M, Shibagaki, I, Nakao, K, Ikenaga, M & Ishizaki, K (1994). Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma. Cancer Res 54: 3107–3110.
Palmero, I & Peters, G (1996). Perturbation of cell cycle regulators in human cancer. Cancer Surveys 27: 351–367.
Quelle, DE, Ashmun, RA, Shurtleff, SA, Kato, JY, Bar-Sagi, D, Roussel, MF & Sherr, CJ (1993). Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev 7: 1559–1571.
Sambrook, J, Fritsch, EF & Maniatis, T (1989). Molecular Cloning: A Laboratory Manual, 2nd edn, Cold Spring Harbor Laboratory Press: Cold Spring Harbor NY, USA
Sawa, H, Ohshima, TA, Ukita, H, Murakami, H, Chiba, Y, Kamanda, H, Hara, M & Saito, I (1998). Alternatively spliced forms of cyclin D1 modulate entry into the cell cycle in an inverse manner. Oncogene 16: 1701–1712.
Sherr, CJ (1996). Cancer cell cycles. Science 274: 1672–1677.
Worsley, S, Ponder, BAJ & Davies, BR (1997). Overexpression of cyclin D1 in epithelial ovarian cancers. Gynecol Oncol 64: 189–195.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Dhar, K., Branigan, K., Parkes, J. et al. Expression and subcellular localization of cyclin D1 protein in epithelial ovarian tumour cells. Br J Cancer 81, 1174–1181 (1999). https://doi.org/10.1038/sj.bjc.6690826
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690826
Keywords
This article is cited by
-
Knockdown of ALPK2 inhibits the development and progression of Ovarian Cancer
Cancer Cell International (2020)
-
Cyclin D as a therapeutic target in cancer
Nature Reviews Cancer (2011)
-
Microenvironment and Pathogenesis of Epithelial Ovarian Cancer
Hormones and Cancer (2010)
-
Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms
Oncogene (2009)
-
Impact of differential cyclin D1 expression and localisation in prostate cancer
British Journal of Cancer (2007)