Elevated and Absent pRb Expression is Associated With Bladder Cancer Progression and has Cooperative Effects With p53

Côté, Richard J.; Dunn, Matthew D.; Chatterjee, Sumana; Stein, John P.; Shi, Shan; Tran, Q.-C.; Hu, Shi Xue; Xu, Hong Ji; Groshen, Susan; Taylor, Clive R.; Skinner, Donald G.; Benedict, William F.

doi:10.1097/00005392-199811000-00096

Cited by 135 publications

(132 citation statements)

References 8 publications

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“…It is well known that hypermethylation involving p16 is a frequent mechanism for loss of p16 expression in several common cancers (Merlo et al, 1995;Reed et al, 1996;Wong et al, 1997) but is substantially less frequent in bladder cancer (Spruck et al, 1994). However, regardless of the mechanism, our data support the hypothesis that loss of p16 protein expression is associated with the overexpression of RB recently reported to have similar biological and clinical signi®cance as loss of RB expression in bladder tumors (Cote et al, 1998;Grossman et al, 1998). Moreover, the relationship between overexpression of RB and loss of p16 function also may extend to other tumor types, particularly to those tumor types for which loss of RB function has been implicated as a key factor in their progression including osteosarcomas, ®brosarcomas and non-small cell lung carcinomas (Benedict et al, 1990).…”

Section: Discussionsupporting

confidence: 88%

“…As stated previously, these latter two studies used the same criteria and methodology to determine the RB status in bladder tumors as was utilized in our present report. It was found that patients whose tumor overexpressed RB protein had a similar increased progression rate and a decreased overall survival as individuals whose tumor was RB negative (Cote et al, 1998;Grossman et al, 1998). This relationship was seen for both super®cial and highly invasive tumors.…”

Section: Discussionmentioning

confidence: 92%

“…Moreover, loss of RB function has been associated with progression to invasive disease and decreased survival (Cordon-Cardo et al, 1992;Logothetis et al, 1992). In addition it was recently found that patients whose bladder cancer showed overexpression of RB protein by immunohistochemical (IHC) analysis had an increased rate of progression and decreased survival rate comparable to those patients with tumors exhibiting no RB protein expression (Cote et al, 1998;Grossman et al, 1998). These ®ndings suggest that bladder tumors with a strong, homogeneous staining pattern may re¯ect abnormal RB status resulting in a similar pathological e ect as those tumors with absent RB protein expression.…”

Section: Introductionmentioning

confidence: 99%

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Recent studies have shown that patients whose bladder cancer exhibit overexpression of RB protein as measured by immunohistochemical analysis do equally poorly as those with loss of RB function. We hypothesized that loss of p16 protein function could be related to RB overexpression, since p16 can induce transcriptional downregulation of RB and its loss may lead to aberrant RB regulation. Conversely, loss of RB function has been associated with high p16 protein expression in several other tumor types. In the present study RB negative bladder tumors also exhibited strong nuclear p16 staining while each tumor with strong, homogeneous RB nuclear staining were p16 negative, supporting our hypothesis. To expand on these immunohistochemical studies additional cases were selected in which the status of the p16 encoding gene had been determined at the molecular level. Absent p16 and high RB protein expression was found in the tumors having loss of heterozygosity within 9p21 and a structural change (mutation or deletion) of the remaining p16 encoding gene allele, con®rming the staining results. These results strongly support the hypothesis that the RB nuclear overexpression recently associated with poor prognosis in bladder cancer is also associated with loss of p16 function and implies that loss of p16 function could be equally deleterious as RB loss in bladder and likely other cancers.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

et al. 1999

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“…In fact, although decreased expression of pRb has been shown to be significantly associated with prognosis (Cordon-Cardo et al, 1992;Logothetis et al, 1992), a recent study on 173 cases failed to find any correlation between pRb and clinical outcome (Jahnson and Karlsson, 1998). However, a combined analysis of p53 and pRb in a large series (Cote et al, 1998) showed that cases with altered expression of pRb had significantly higher recurrence (P ¼ 0.0001) and lower survival rates (P ¼ 0.0002) compared to cases with normal pRb expression. Moreover, patients with alteration of both p53 and pRb had significantly increased rates of recurrence (Po0.0001) and decreased survival (Po0.0001) compared to patients with no alterations in either p53 or pRb; patients with alteration in only one of these proteins had intermediate rates of recurrence and survival.…”

Section: Malignancies Of the Urinary Tractmentioning

confidence: 98%

RB family members as predictive and prognostic factors in human cancer

2006

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“…It is well known that pRb-negative tumor cells tend to have low levels of cyclin D1, 49 -51 and it was previously shown that bladder cancers overexpressing cyclin D1 retain the pRb protein. 29 Loss of Rb has been reported to be an important prognostic factor in primary superficial bladder cancer; 52,53 it is possible that low expression of cyclin D1 simply identifies tumors with loss of pRb, which is the real driving force affecting tumor progression. Studies are ongoing to evaluate pRb expression in our series of tumors and verify this hypothesis.…”

Section: Predictive Power Of Combined Cyclin D1 P27 Kip1 and Ki67 Indexmentioning

confidence: 99%

Cyclin D1 expression in papillary superficial bladder cancer: Its association with other cell cycle‐associated proteins, cell proliferation and clinical outcome

Sgambato

Migaldi

Faraglia

et al. 2001

Intl Journal of Cancer

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Cyclin D1 contributes to regulate G1 progression by forming a complex with different cyclin-dependent kinases. It has oncogenic properties and is frequently overexpressed in several human tumor types. In our study, expression of cyclin D1 and Ki67, a proliferation marker, was evaluated by immunohistochemistry in human papillary superficial (pTa-pT1) bladder cancers and was correlated with p27 Kip1 , p21 Waf1 and c-erbB-2 expression, with p53 gene status and protein expression, ploidy and cancer progression. Cyclin D1 expression was neither associated with tumor stage nor with tumor grade but high cyclin D1 expression (>25% positive nuclei) was significantly associated with p53 gene mutation (p ‫؍‬ 0.012), low p21 Waf1 (p ‫؍‬ 0.015) and high p27 Kip1 (p ‫؍‬ 0.016) protein expression. Ki67 expression was not associated with tumor stage but a high proliferation index (>10% positive nuclei) was significantly associated with high tumor grade (p ‫؍‬ 0.001) and with DNA aneuploidy (p ‫؍‬ 0.005). There was no significant difference in proliferative activity between high and low cyclin D1 expressor tumors. Patients whose tumors showed high expression of cyclin D1 displayed a significantly longer disease-free survival (p < 0.001 by log-rank test). Increased Ki67 expression was significantly associated with shorter disease-free survival (p ‫؍‬ 0.003). Both cyclin D1 (p ‫؍‬ 0.027; RR ‫؍‬ 1.898) and Ki67 (p ‫؍‬ 0.047; RR ‫؍‬ 1.932) protein expressions were independent predictors of reduced diseasefree survival on a multivariate analysis that also included p27 Kip1 expression and tumor stage. The simultaneous presence of low cyclin D1, low p27 Kip1 and high Ki67 expression defined a "high-risk" group of patients who displayed a significantly increased risk of recurrence (p < 0.0001). These results suggest that evaluation of cell cycle-associated markers can help to identify high-risk patients and may affect the management of patients with papillary superficial bladder cancer.

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Elevated and Absent pRb Expression is Associated With Bladder Cancer Progression and has Cooperative Effects With p53

Cited by 135 publications

References 8 publications

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

RB family members as predictive and prognostic factors in human cancer

Cyclin D1 expression in papillary superficial bladder cancer: Its association with other cell cycle‐associated proteins, cell proliferation and clinical outcome

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