p53, bcl-2 and Retinoblastoma Proteins as Long-Term Prognostic Markers in Localized Carcinoma of the Prostate

Theodorescu, Dan; Broder, Stanford R.; Boyd, James C.; Mills, Stacey E.; Frierson, Henry F.

doi:10.1097/00005392-199707000-00040

Cited by 127 publications

(65 citation statements)

References 30 publications

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“…It has been proposed that downregulation of pRB represents an early event in prostate cancer development and loss of pRB is a prognostic marker of cancer progression (Brooks et al, 1995;Theodorescu et al, 1997). Loss of expression of p16, a CDK inhibitor and upstream regulator of pRB, is also of prognostic significance in locally advanced prostate cancer (Chakravarti et al, 2003), with the downregulation of p16 expression probably resulting from gene hypermethylation or gene deletion (Konishi et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Mutation and altered expression of other upstream regulators of pRB such as p53, p21 and MDM2 (Gao et al, 1995;Osman et al, 1999;Leite et al, 2001) have also been observed in prostate cancer, although mutations in the p53 gene are most frequently associated with metastatic and hormone-refractory disease (Heidenberg et al, 1995). It is particularly significant that prostate cancer exhibits both downregulation of pRB (Brooks et al, 1995;Theodorescu et al, 1997) and overexpression of E2F3. In bladder cancer, it appears that E2F3 overexpression and pRB inactivation can occur in the same tumours, and we have proposed that cooperation between these two events is required for bladder carcinogenesis (Feber et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…signifies that the indicated change in gene expression is associated with adverse clinical outcome (see Theodorescu et al, 1997;Varambally et al, 2002;Chakravarti et al, 2003) followed by deionized water. High-temperature antigen retrieval was then performed in a pressure-cooker, and comprised heating for 3 min at full pressure (103 kPa) in 10 mM EDTA buffer (pH 7.0).…”

Section: Immunohistochemistrymentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

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Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome

et al. 2004

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“…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). For prostate cancer, it has been proposed that downregulation of pRB represents an early event in prostate cancer development and loss of pRB is a prognostic marker for cancer development (Theodorescu et al, 1997). Loss of expression of p16 an upstream regulator of pRB is also of prognostic significance in locally advanced disease (Chakravarti et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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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“…Moreover, abnormal bcl-2 or bax expression was not significantly associated with Gleason Score or stage; although a borderline relationship of bax expression to Gleason Score was observed (Table 3). While some relationships of these biomarkers to Gleason Score have been reported (9,(22)(23)(24), this has not been a consistent finding (25)(26)(27). In a report of patients with Stage B, C, or D disease, Amirghofran et al (28) found that bax, but not bcl-2 expression, was significantly related to prostate carcinoma stage (p = 0.031); no correlation to Gleason Score was observed for either biomarker.…”

Section: Discussionmentioning

confidence: 95%

Bcl-2 and bax expression and prostate cancer outcome in men treated with radiotherapy in Radiation Therapy Oncology Group protocol 86-10

Khor

DeSilvio

et al. 2006

International Journal of Radiation Oncology*Biology*Physics

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Purpose-Bcl-2 and bax are proteins with opposing roles in apoptosis regulation; yet abnormal expression of either has been associated with failure after radiotherapy (RT). In this study we examined bcl-2 and bax expression as predictive markers in men treated with radiotherapy ± androgen deprivation on Radiation Therapy Oncology Group (RTOG) protocol 86-10.Experimental Design-Suitable archival diagnostic tissue was obtained from 119 (26%) patients for bcl-2 analysis and 104 (23%) patients for bax analysis. Cox proportional hazards multivariate analysis was used to determine the relationship of abnormal bcl-2 and bax expression to the end points of local failure, distant metastasis, cause-specific mortality, and overall mortality. Bcl-2 overexpression was classified as any tumor cell cytoplasmic staining and altered bax expression was classified as greater or lesser cytoplasmic staining intensity of tumor cells as compared with adjacent normal prostate epithelium.Results-The study cohort exhibited bcl-2 overexpression in 26% (n = 30) of cases and abnormal bax expression in 47% (n = 49) of cases. A borderline significant relationship was observed between abnormal bax expression and higher Gleason score (p = 0.08). In univariate and multivariate analyses, there was no statistically significant relationship seen between abnormal bcl-2 or bax expression and outcome. Conclusions-Abnormal bcl-2 and bax expression were not related to any of the end points tested. The cohort examined was comprised of patients with locally advanced disease and it is possible that these markers may be of greater value in men with earlier-stage prostate cancer.

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p53, bcl-2 and Retinoblastoma Proteins as Long-Term Prognostic Markers in Localized Carcinoma of the Prostate

Cited by 127 publications

References 30 publications

Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome

Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome

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

Bcl-2 and bax expression and prostate cancer outcome in men treated with radiotherapy in Radiation Therapy Oncology Group protocol 86-10

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