Abstract
We analysed p16 gene alteration and p16, cyclin-dependent kinase 4 (CDK4), CDK6, cyclin D1, cyclin D2, cyclin D3 and retinoblastoma protein (pRb) expression in ten normal endometriums (PE), 18 endometrial hyperplasias (EH) and 35 endometrial cancers (EC). Two of ten PE (20%), nine of 18 EH (50.0%) and 29 of 35 EC (82.9%) exhibited p16 nuclear staining. p16 expression was significantly higher in EC than EH (P = 0.0119). In the six p16 (–) EC, one was considered to have reduced gene dosage consistent with possible homozygous deletion of the CDKN2 gene and three had methylation in 5′CpG island in the promoter region of the p16 gene, whereas none showed such reduced gene dosage and four had methylation in the nine p16 (–) EH. Strong CDK4 staining was observed in 12 of 35 EC (34.3%) and one of 18 EH (5.6%). The strong expression of CDK4 was higher in EC than in EH (P = 0.0399). The expression of CDK4 was higher in EH than PE (P = 0.0054). The abnormalities of p16-cyclin D/CDK-pRb pathway were detected in 18 of 35 EC (51.4%). In conclusion, the expression of p16 and CDK4 may be an early event in the neoplastic transformation of endometrial cancer. © 2000 Cancer Research Campaign
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 and Alama A (1997) Expression of cyclin D1 correlates with malignancy in human ovarian tumours. Br J Cancer 75: 1263–1268
Bartkova J, Lukas J, Guldberg P, Alsner J, Kirkin AF, Zeuthen J and Bartek J (1996) The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis. Cancer Res 56: 5475–5483
Buckley M, Sweeney KJE, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CKW, Musgrove EA and Sutherland RL (1993) Expression and amplification of cyclin genes in human breast cancer. Oncogene 8: 2127–2133
Cairns P, Poladcik TJ, Eby Y, Tokino K, Califano J, Merlo A, Mao L, Herath J, Jenkins R and Westra W (1995) Frequency of homozygous deletion at p16/CDKN2 in primary human tumors. Nat Genet 11: 210–212
Campbell IG, Beynon G, Davis M and Englefield P (1995) LOH and mutation analysis of CDKN2 in primary human ovarian cancer. Int J Cancer 63: 222–225
Cirns P (1995) Frequency of homozygous deletion at p16/CDKN2 in primary human tumors. Nat Genet 11: 210–212
Dutta A, Chandra R, Leiter LM and Lester S (1995) Cyclins as markers of tumor proliferation: immunocytochemical studies in breast cancer. Proc Natl Acad Sci USA 92: 5386–5390
Geradts J, Kratzke RA, Crush-Stanton S, Wen SF and Lincoln CE (1996) Wild-type and mutant retinoblastoma protein in paraffin sections. Mod Pathol 9: 339–347
Gillett C (1996) Cyclin D1 and prognosis in breast cancer. Int J Cancer 69: 92–99
Gnozalez-Zulueta M, Bender CM, Yang AS, Nguyen T, Beart RW, Van Tornout JM and Jones PA (1995) Methylation of the 5′CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res 55: 4531–4535
Hall M and Peters G (1996) Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res 68: 67–108
He J, Allen JR, Collins VP, Allalunis-Turner MJ, Godbout R, Day RS and James CD (1994) CDK4 amplification is an alternative mechanism to p16 homozygous deletion in glioma cell lines. Cancer Res 54: 5804–5807
Herman JG, Merlo A, Mao L, Lapidus RG, Issa J-PJ, Davidson NE, Sidransky D and Baylin SB (1995) Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 55: 4525–4530
Hui R, Cornish AL, McClelland RA, Robertson JFR, Blamey RW, Musgrove EA, Nicholson RI and Sutherland RL (1996) Cyclin D1 and estrogen receptor messenger RNA levels are positively correlated in primary breast cancer. Clin Cancer Res 2: 923–928
Hussussian CJ, Struewing JP, Goldstein AM, Higgins PAT and Ally DS (1994) Germline p16 mutations in familial melanoma. Nature Genet 8: 15–21
Jiang W, Zhang YJ, Kahn SM, Hollstein MC, Santella RM, Lu SH, Harris CC, Montesano R and Weinstein IB (1993) Altered expression of the cyclin D1 and retinoblastoma genes in human esophageal cancer. Proc Natl Acad Sci USA 90: 9026–9030
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stocker E, Day RS, III Johnson BE and Skolnick MH (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264: 436–440
Kamb A (1995) Cell-cycle regulators and cancer. Trends Genet 11: 136–140
Kinoshita I, Dosaka-Akita H, Mishina T, Akie K, Nishi M, Hiroumi H, Hommura F and Kawakami Y (1996) Altered p16INK4and retinoblastoma protein status in non-small cell lung cancer: potential synergistic effect with altered p53 protein on proliferative activity. Cancer Res 56: 5557–5562
Kratzke RA, Greatens TM, Rubins JB, Maddaus MA, Niewoehner DE, Niehans GA and Geradts J (1996) Rb and p16INK4Aexpression in resected non-small cell lung tumors. Cancer Res 56: 3415–3420
Li Y, Nicholos MA, Shay JW and Xiong Y (1994) Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRB. Cancer Res 54: 6078–6082
McIntosh GG, Anderson JJ, Milton I, Steward M, Parr AH, Thomas MD, Henry JA, Angus B, Lennard TWJ and Horne CHW (1995) Determination of the prognostic value of cyclin D1 overexpression in breast cancer. Oncogene 11: 885–891
Maestro R and Boiocchi M (1995) Sunlight and melanoma: an answer from MTS1 (p16). Science 267: 15–16
Marchini S, Codegoni AM, Bonazzi C, Chiari S and Broggini M (1997) Absence of deletions but frequent loss of expression of p16INK4in human ovarian tumours. Br J Cancer 76: 146–149
Michalides R, van Veelen N, Hart A, Loftus B, Wientjens E and Balm A (1995) Overexpression of cyclin D1 correlates with recurrence in a group of forty-seven operable squmaous cell carcinomas of the head and neck. Cancer Res 55: 975–978
Milde-Langosch K, Riethdorf L, Bamberger AM and Loning T (1999) P16/MTS1 and pRB expression in endometrial carcinomas. Virchows Arch 434: 23–28
Muller H, Lukas J, Schneider A, Warthoe P, Bartek J, Eilers M and Strauss M (1994) Cyclin D1 expression is regulated by the retinoblastoma protein. Proc Natl Acad Sci USA 91: 2945–2949
Nakagawa K, Conrad NK, Williams JP, Johnson BE and Kelly MJ (1995) Mechanism of inactivation of CDKN2 and MTS2 in non-small-cell lung cancer and association with advanced stage. Oncogene 11: 1843–1851
Niemann TH, Yilmaz AG, McGaughy VR and Vaccarello L (1997) Retinoblastoma protein expression in endometrial carcinoma. Gynecol Oncol 65: 232–236
Peiffer SL, Bartsch D, Whelan AJ, Mutch DG, Herzog TJ and Goodfellow PJ (1995) Low frequency of CDKN2 mutation in endometrial carcinomas. Mol Carcinog 13: 210–212
Pietilainen T, Lipponen P, Aaltomaa S, Eskelinen M, Kosma VM and Syrjanen K (1995) Expression of retinoblastoma gene protein (Rb) in breast cancer as related to established prognostic factors and survival. Eur J Cancer 31A: 329–333
Prall OWJ, Sarcevic B, Musgrove EA, Watts CKW and Sutherland RL (1997) Estrogen-induced activation of Cdk4 and Cdk3 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem 272: 10882–10894
Schauer IE, Siriwardana S, Langan TA and Sclafani RI (1994) Cyclin D1 overexpression vs. retinoblastoma inactivation: implications for growth control evasion in non-small and small cell lung cancer. Proc Natl Acad Sci USA 91: 7827–7831
Serrano M, Hannon GJ and Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclinD/CDK4. Nature 366: 704–707
Sherr CJ and Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Gene Dev 9: 1149–1163
Shigemasa K, Hu C, West CM, Clarke J, Parham GP, Parmley TH, Korourian S, Baker VV and O'Brien TJ (1997) p16 overexpression: a potential early indicator of transformation in ovarian carcinoma. J Soc Gynecol Invest 4: 95–102
Shiozawa T, Nikaido T, Shimizu M, Zhai Y and Fujii S (1997) Immunohistochemical analysis of the expression of CDK4 and p16INK4in human endometrioid-type endometrial carcinoma. Cancer 80: 2250–2256
Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, Haslam SZ, Bronson RT, Elledge SJ and Weinberg RA (1995) Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82: 621–630
Strauss M, Lukas J and Bartek J (1995) Unrestricted cell cycling and cancer. Nat Med 1: 1245–1246
Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A and Schmidt EV (1994) Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature (Lond) 369: 669–671
Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell 81: 323–330
Yao J, Pollock RE, Lang A, Ming T, Pisters PWT, Goodrich D, El-Naggar A and Yu DIHUA (1998) Infrequent mutation of the p16/MTS1 gene and overexpression of cyclin-dependent kinase 4 in human primary soft-tissue sarcoma. Clin Cancer Res 4: 1065–1070
Yaginuma Y, Katayama H, Kawai K, Duenas JC and Ishikawa M (1996) Analysis of the retinoblastoma gene in human endometrial carcinoma. Obstet Gynecol 87: 755–759
Zhang T, Nanney LB, Luongo C, Lamps Heppner KJ, DuBois RN and Beauchamp RD (1997) Concurrent overexpression of cyclinD1 and cyclin-dependent kinase 4 (Cdk4) in intestinal adenomas from multiple intestinal neoplasia (Min) mice and human familial adenomatous polyposis patients. Cancer Res 57: 169–175
Zuberberg LR, Yang WI, Gadd M, Thor AD, Koerner FC, Schmidt EV and Arnold A (1995) Cyclin D1 (PRAD1) protein expression in breast cancer: approximately one-third of infiltrating mammary carcinomas show overexpression of the cyclin D1 oncogene. Mod Pathol 8: 560–566
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
Tsuda, H., Yamamoto, K., Inoue, T. et al. The role of p16-cyclin D/CDK-pRb pathway in the tumorigenesis of endometrioid-type endometrial carcinoma. Br J Cancer 82, 675–682 (2000). https://doi.org/10.1054/bjoc.1999.0980
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1054/bjoc.1999.0980
Keywords
This article is cited by
-
Feasibility of endometrial sampling by vaginal tampons in women with Lynch syndrome
BMC Women's Health (2020)
-
HOXB9 promotes endometrial cancer progression by targeting E2F3
Cell Death & Disease (2018)
-
Prognostic importance of CDK4/6-specific activity as a predictive marker for recurrence in patients with endometrial cancer, with or without adjuvant chemotherapy
British Journal of Cancer (2015)
-
Aberrant promoter hypermethylation of p16 gene in endometrial carcinoma
Tumor Biology (2015)
-
Emerging therapeutic targets in endometrial cancer
Nature Reviews Clinical Oncology (2011)
