Abstract
E2F3 is located in the 6p22 bladder amplicon and encodes a transcription factor important for cell cycle regulation and DNA replication. To further investigate the role of E2F3 in bladder cancer, a tissue microarray containing samples from 2317 bladder tumors was used for gene copy number and expression analysis by means of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). E2F3 amplification was strongly associated with invasive tumor phenotype and high tumor grade (P<0.0001 each). None of 272 pTaG1/G2 tumors, but 35 of 311 pT1-4 carcinomas (11.3%), had E2F3 amplification. A high E2F3 expression level was associated with high grade, advanced stage, and E2F3 gene amplification (P<0.0001 each). To evaluate whether E2F3 expression correlates with tumor proliferation, the Ki67 labeling index (LI) was analysed for each tumor. There was a strong association between a high Ki67 LI and E2F3 expression (P<0.0001), which was independent of grade and stage. We conclude that E2F3 is frequently amplified and overexpressed in invasively growing bladder cancer (stage pT1-4). E2F3 expression appears to provide a growth advantage to tumor cells by activating cell proliferation in a subset of bladder tumors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Anantharaman V, Koonin EV and Aravind L . (2001). FEMS Microbiol. Lett., 197, 215–221.
Bruch J, Schulz WA, Haussler J, Melzner I, Bruderlein S, Moller P, Kemmerling R, Vogel W and Hameister H . (2000). Cancer Res., 60, 4526–4530.
Bubendorf L, Grilli B, Sauter G, Mihatsch MJ, Gasser TC and Dalquen P . (2001). Am. J. Clin. Pathol., 116, 79–86.
Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC and Croce CM . (1982). Proc. Natl. Acad. Sci. USA, 79, 7824–7827.
DiMattia GE, Gellersen B, Duckworth ML and Friesen HG . (1990). J. Biol. Chem., 265, 16412–16421.
Farr CJ, Easty DJ, Ragoussis J, Collignon J, Lovell-Badge R and Goodfellow PN . (1993). Mamm. Genome, 4, 577–584.
Halling KC, King W, Sokolova IA, Meyer RG, Burkhardt HM, Halling AC, Cheville JC, Sebo TJ, Ramakumar S, Stewart CS, Pankratz S, O'Kane DJ, Seelig SA, Lieber MM and Jenkins RB . (2000). J. Urol., 164, 1768–1775.
Hui R, Campbell DH, Lee CS, McCaul K, Horsfall DJ, Musgrove EA, Daly RJ, Seshadri R and Sutherland RL . (1997). Oncogene, 15, 1617–1623.
Humbert PO, Verona R, Trimarchi JM, Rogers C, Dandapani S and Lees JA . (2000). Genes Dev., 14, 690–703.
Kallioniemi A, Kallioniemi O, Citro G, Sauter G, DeVries S, Kerschmann R, Carroll P and Waldman F . (1995). Genes Chromosomes Cancer, 12, 213–219.
Kallioniemi A, Kallioniemi O, Sudar D, Rutovitz D, Gray J, Waldman F and Pinkel D . (1992). Science, 258, 818–821.
Kondo I and Shimizu N . (1983). Cytogenet. Cell Genet., 35, 9–14.
Kononen J, Bubendorf L, Kallioniemi A, Bärlund M, Schraml P, Leighton S, Torhorst J, Mihatsch M, Sauter G and Kallioniemi O . (1998). Nat. Med., 4, 844–847.
Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N and Helin K . (1993). Mol. Cell. Biol., 13, 7813–7825.
Leone G, DeGregori J, Yan Z, Jakoi L, Ishida S, Williams RS and Nevins JR . (1998). Genes Dev., 12, 2120–2130.
Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park CH, Giangrande P, Wu L, Saavedra HI, Field SJ, Thompson MA, Yang H, Fujiwara Y, Greenberg ME, Orkin S, Smith C and Nevins JR . (2001). Mol. Cell, 8, 105–113.
Lipponen PK, Eskelinen MJ, Jauhiainen K, Terho R and Nordling S . (1993). Br. J. Urol., 72, 451–457.
Liukkonen T, Rajala P, Raitanen M, Rintala E, Kaasinen E and Lipponen P . (1999). Eur. Urol., 36, 393–400.
Mitelman F . (1994). Catalog of Chromosome Aberrations in Cancer, 5th edn. Wiley-Liss: New York.
Moch H, Sauter G, Gasser T, Buchholz N, Bubendorf L, Richter J, Jiang F, Dellas A and Mihatsch M . (1997). Urol. Res., 25, S25–S30.
Mostofi F . (1973). Histological Typing of Urinary Bladder Tumors. World Health Organization: Geneva.
Nakopoulou L, Vourlakou C, Zervas A, Tzonou A, Gakiopoulou H and Dimopoulos MA . (1998). Hum. Pathol., 29, 146–154.
Nevins JR . (1998). Cell Growth Differ., 9, 585–593.
Nocito A, Bubendorf L, Maria Tinner E, Suess K, Wagner U, Forster T, Kononen J, Fijan A, Bruderer J, Schmid U, Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Anabitarte M, Hering F, Hardmeier T, Schoenenberger AJ, Flury R, Jager P, Luc Fehr J, Schraml P, Moch H, Mihatsch MJ, Gasser T and Sauter G . (2001). J. Pathol., 194, 349–357.
Pfister C, Buzelin F, Casse C, Bochereau G, Buzelin JM and Bouchot O . (1998). Eur. Urol., 33, 278–284.
Polanowska J, Le Cam L, Orsetti B, Valles H, Fabbrizio E, Fajas L, Taviaux S, Theillet C and Sardet C . (2000). Genes Chromosomes Cancer, 28, 126–130.
Popescu NC, King CR and Kraus MH . (1989). Genomics, 4, 362–366.
Rabbani F, Richon VM, Orlow I, Lu ML, Drobnjak M, Dudas M, Charytonowicz E, Dalbagni G and Cordon-Cardo C . (1999). J. Natl. Cancer Inst., 91, 874–881.
Reifenberger G, Reifenberger J, Ichimura K, Meltzer PS and Collins VP . (1994). Cancer Res., 54, 4299–4303.
Richter J, Beffa L, Wagner U, Schraml P, Gasser T, Moch H, Mihatsch M and Sauter G . (1998). Am. J. Pathol., 153, 1615–1621.
Richter J, Jiang F, Görög J, Sartorius G, Moch H, Egenter C, Gasser T, Mihatsch M and Sauter G . (1997). Cancer Res., 57, 2860–2864.
Richter J, Wagner U, Kononen J, Fijan A, Bruderer J, Schmid U, Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Wilber K, Anabitarte M, Hering F, Hardmeier T, Schonenberger A, Flury R, Jager P, Fehr JL, Schraml P, Moch H, Mihatsch MJ, Gasser T, Kallioniemi OP and Sauter G . (2000). Am. J. Pathol., 157, 787–794.
Richter J, Wagner U, Schraml P, Maurer R, Gasser T, Moch H, Mihatsch M and Sauter G . (1999). Cancer Res., 59, 5687–5691.
Saito M, Helin K, Valentine MB, Griffith BB, Willman CL, Harlow E and Look AT . (1995). Genomics, 25, 130–138.
Sauter G, Moch H, Mihatsch M, Kerschmann R, Carroll P and Waldman F . (1994). Path. Res. Pract., 190, 281–282.
Simon R, Atefy R, Wagner U, Forster T, Fijan A, Bruderer J, Wilber K, Mihatsch MJ, Gasser T and Sauter . (2003). Int. J. Cancer, 107, 764–772.
Simon R, Bürger H, Brinkschmidt C, Böcker W, Hertle L and Terpe H . (1998). J. Pathol., 185, 345–351.
Simon R, Burger H, Semjonow A, Hertle L, Terpe HJ and Bocker W . (2000). Int. J. Oncol., 17, 1025–1029.
Simon R, Richter J, Wagner U, Fijan A, Bruderer J, Schmid U, Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Wilber K, Anabitarte M, Hering F, Hardmeier T, Schonenberger A, Flury R, Jager P, Fehr JL, Schraml P, Moch H, Mihatsch MJ, Gasser T and Sauter G . (2001). Cancer Res., 61, 4514–4519.
Simon R, Struckmann K, Schraml P, Wagner U, Forster T, Moch H, Fijan A, Bruderer J, Wilber K, Mihatsch MJ, Gasser T and Sauter G . (2002). Oncogene, 21, 2476–2483.
Terracciano L, Richter J, Tornillo L, Beffa L, Diener PA, Maurer R, Gasser TC, Moch H, Mihatsch MJ and Sauter G . (1999). J. Pathol., 189, 230–235.
Trimarchi JM and Lees JA . (2002). Nat. Rev. Mol. Cell Biol., 3, 11–20.
UICC (1992). TNM Classification of Malignant Tumours, 4th edn Springer: Berlin.
Veltman JA, Fridlyand J, Pejavar S, Olshen AB, Korkola JE, DeVries S, Carroll P, Kuo WL, Pinkel D, Albertson D, Cordon-Cardo C, Jain AN and Waldman FM . (2003). Cancer Res., 63, 2872–2880.
Voorter C, Joos S, Bringuier PP, Vallinga M, Poddighe P, Schalken J, du Manoir S, Ramaekers F, Lichter P, Hopman A, Voorter C, Joos S, Bringuier PP, Vallinga M, Poddighe P, Schalken J, du Manoir S, Ramaekers F, Lichter P and Hopman A . (1995). Am. J. Pathol., 146, 1341–1354.
Wagner U, Bubendorf L, Gasser T, Moch H, Görög J, Mihatsch M, Waldman F and Sauter G . (1997). Am. J. Pathol., 151, 753–759.
Wu L, Timmers C, Maiti B, Saavedra HI, Sang L, Chong GT, Nuckolls F, Giangrande P, Wright FA, Field SJ, Greenberg ME, Orkin S, Nevins JR, Robinson ML and Leone G . (2001). Nature, 414, 457–462.
Xiong Y, Menninger J, Beach D and Ward DC . (1992). Genomics, 13, 575–584.
Zaharieva BM, Simon R, Diener PA, Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Wilber K, Hering F, Schonenberger A, Flury R, Jager P, Fehr JL, Mihatsch MJ, Gasser T, Sauter G and Toncheva DI . (2003). J. Pathol., 201, 603–608.
Zhao J, Richter J, Wagner U, Ackermann D, Schmid U, Roth B, Moch H, Mihatsch M, Gasser T and Sauter G . (1999). Cancer Res., 59, 4658–4661.
Acknowledgements
We thank Sarina Meinen, Carole Egenter, Yvonne Knecht, Martina Mirlacher, Hedvika Novotny, Heidi Oggier, and Martina Storz for their excellent technical support. Andrew Mungall, Sanger Centre, Cambridge, UK, kindly provided BAC clone dJ177P22. This study was supported by Swiss National Science Foundation (31-56017.98).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Oeggerli, M., Tomovska, S., Schraml, P. et al. E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer. Oncogene 23, 5616–5623 (2004). https://doi.org/10.1038/sj.onc.1207749
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1207749
Keywords
This article is cited by
-
Discovery of IHMT-337 as a potent irreversible EZH2 inhibitor targeting CDK4 transcription for malignancies
Signal Transduction and Targeted Therapy (2023)
-
The multifaceted roles of cohesin in cancer
Journal of Experimental & Clinical Cancer Research (2022)
-
mRNA–miRNA bipartite networks reconstruction in different tissues of bladder cancer based on gene co-expression network analysis
Scientific Reports (2022)
-
A novel LncRNA transcript, RBAT1, accelerates tumorigenesis through interacting with HNRNPL and cis-activating E2F3
Molecular Cancer (2020)
-
EZH2 overexpression dampens tumor-suppressive signals via an EGR1 silencer to drive breast tumorigenesis
Oncogene (2020)