Amplification and overexpression of E2F3 in human bladder cancer

Feber, Andrew; Clark, Jeremy; Goodwin, Graham H.; Dodson, Andrew; Smith, Paul; Fletcher, A.; Edwards, Steven M.; Flohr, Penny; Falconer, Alison; Roe, Toby; Kovács, Gyula; Dennis, Nening M.; Fisher, Cyril; Wooster, Richard; Huddart, Robert; Foster, Christopher S.; Cooper, Christopher S.

doi:10.1038/sj.onc.1207274

Cited by 145 publications

(133 citation statements)

References 25 publications

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“…In a previous study, we reported amplification of both E2F3 and CDKAL1 genes in the TCCSUP, 5637 and HT1376 bladder cancer cell lines (Feber et al, 2004). We also demonstrated that in all these three cell lines, amplification of the E2F3 gene was accompanied by E2F3 mRNA overexpression and high-level expression of the E2F3 proteins.…”

Section: Knockdown Of Mrna In Bladder Cancer Cells Containing Amplifisupporting

confidence: 62%

“…The presence of this amplification was shown to correlate with tumour grade Prat et al, 2001) and, in high-grade cancers, with tumour cell proliferation rate (Tomovska et al, 2001). Initial mapping studies indicated that the 6p22 amplicon spanned the SOX4, PRL and E2F3 genes (Bruch et al, 2000;Veltman et al, 2003) and in CGH studies onto cDNA microarrays, we found that only two genes from this region, E2F3 and CDKAL1/FLJ20342 (hereafter called CDKAL1), were consistently amplified in bladder cancers (Feber et al, 2004). Amplification of E2F3 was accompanied by overexpression of the mRNA transcripts and E2F3 protein.…”

Section: Introductionmentioning

confidence: 59%

“…Immunohistochemical analyses of the E2F3 protein levels established that one-third of primary transition cell carcinomas of the bladder overexpressed nuclear E2F3 protein, with the proportion of tumour containing nuclear E2F3 increasing with tumour stage and grade. When considered together with the established role of E2F3 in controlling cell cycle progression, we proposed that E2F3 represented the target gene within the 6p22 amplicon in human bladder cancer (Feber et al, 2004). Oeggerli et al (2004) reported similar results, and on the basis of parallel analyses of E2F3 protein and the proliferation marker Ki67 suggested that E2F3 overexpression may provide a growth advantage to tumour cells by activating cellular proliferation in a subset of bladder cancers.…”

Section: Introductionmentioning

confidence: 83%

“…For both bladder and prostate cancer, we have proposed a model for cancer development in which overexpression of E2F3 cooperates with removal of the retinoblastoma tumour suppressor protein (pRB) suppressor control at the G1/S transition in the cell cycle (Feber et al, 2004;Foster et al, 2004). In addition to removal of RB1 itself, many of the genetic changes found in bladder cancer may indirectly lead to pRB inactivity, for example, elevating cyclin D1, removing the cyclin-dependent kinase (CDK) inhibitor p16, mutating the TP53 gene or amplifying and overexpressing MDM2 (Knowles, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

et al. 2006

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Amplification and overexpression of the E2F3 gene at 6p22 in human bladder cancer is associated with increased tumour stage, grade and proliferation index, and in prostate cancer E2F3 overexpression is linked to tumour aggressiveness. We first used small interfering RNA technology to confirm the potential importance of E2F3 overexpression in bladder cancer development. Knockdown of E2F3 expression in bladder cells containing the 6p22 amplicon strongly reduced the extent of bromodeoxyuridine (BrdU) incorporation and the rate of cellular proliferation. In contrast, knockdown of CDKAL1/ FLJ20342, another proposed oncogene, from this amplicon had no effect. Expression cDNA microarray analysis on bladder cancer cells following E2F3 knockdown was then used to identify genes regulated by E2F3, leading to the identification of known E2F3 targets such as Cyclin A and CDC2 and novel targets including pituitary tumour transforming gene 1, Polo-like kinase 1 (PLK1) and Caveolin-2. For both bladder and prostate cancer, we have proposed that E2F3 protein overexpression may cooperate with removal of the E2F inhibitor retinoblastoma tumor suppressor protein (pRB) to drive cellular proliferation. In support of this model, we found that ectopic expression of E2F3a enhanced the BrdU incorporation, a marker of cellular proliferation rate, of prostate cancer DU145 cells, which lack pRB, but had no effect on the proliferation rate of PC3 prostate cancer cells that express wild-type pRB. BrdU incorporation in PC3 cells could, however, be increased by overexpressing E2F3a in cells depleted of pRB. When taken together, these observations indicate that E2F3 levels have a critical role in modifying cellular proliferation rate in human bladder and prostate cancer.

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Section: Knockdown Of Mrna In Bladder Cancer Cells Containing Amplifisupporting

confidence: 62%

Section: Introductionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

et al. 2006

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“…We recently demonstrated that amplification and overexpression of E2F3 may represent a facilitating mechanism in the genesis of bladder carcinogenesis (Feber et al, 2004). High levels of expression of E2F3 were observed in approximately one-third of transitional cell carcinomas of the bladder, with the proportion of each tumour exhibiting E2F3 overexpression increasing with tumour grade and stage.…”

Section: Introductionmentioning

confidence: 99%

Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome

et al. 2004

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E2F transcription factors, including E2F3, directly modulate expression of EZH2. Recently, overexpression of the EZH2 gene has been implicated in the development of human prostate cancer. In tissue microrarray studies we now show that expression of high levels of nuclear E2F3 occurs in a high proportion (98/147, 67%) of human prostate cancers, but is a rare event in non-neoplastic prostatic epithelium suggesting a role for E2F3 overexpression in prostate carcinogenesis. Patients with prostate cancer exhibiting immunohistochemically detectable nuclear E2F3 expression have poorer overall survival (P ¼ 0.0022) and cause-specific survival (P ¼ 0.0047) than patients without detectable E2F3 expression. When patients are stratified according to the maximum percentage of E2F3-positive nuclei identified within their prostate cancers (up to 20, 21-40%, etc.), there is an increasingly significant association between E2F3 staining and risk of death both for overall survival (P ¼ 0.0014) and for causespecific survival (P ¼ 0.0004). Multivariate analyses select E2F3 expression as an independent factor predicting overall survival (unstratified P ¼ 0.0103, stratified P ¼ 0.0086) and cause-specific survival (unstratified P ¼ 0.0288, stratified P ¼ 0.0072). When these results are considered together with published data on EZH2 and on the E2F3 control protein pRB, we conclude that the pRB-E2F3-EZH2 control axis may have a critical role in modulating aggressiveness of individual human prostate cancer.

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Bladder Cancer

2006

Wiley Handbook of Current and Emerging Drug Therapies

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Amplification and overexpression of E2F3 in human bladder cancer

Cited by 145 publications

References 25 publications

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome

Bladder Cancer

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