Significance of Cyclin D1 Overexpression in Transitional Cell Carcinomas of the Urinary Bladder and its Correlation With Histopathologic Features

Lee, C.C.R.; Yamamoto, Shinji; Morimura, Keiichirou; Wanibuchi, Hideki; Nishisaka, Nobuyasu; Ikomoto, S.; Nakatani, Tatsuya; Wada, Seiji; Kishimoto, Toshifumi; Fukushima, Shoji

doi:10.1097/00005392-199805000-00111

Cited by 31 publications

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“…Increased expression of cyclin D1 is frequently associated with 11q13 amplification, 26 and a strong relationship was found between cyclin D1 protein and mRNA expression in bladder cancer. 9 However, it has been demonstrated that tumors without amplification can display a high expression of the protein, suggesting that amplification is not the only mechanism leading to overexpression of cyclin D1 in bladder cancer. 10 Experimental evidence has suggested that cyclin D1 can function as an oncogene and that increased expression of cyclin D1 accelerates the G1 phase and likely provides a proliferative advantage to tumor cells.…”

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

confidence: 99%

“…8 Cyclin D1 gene product contributes to the regulation of the G1/S-phase transition of the cell cycle and is a candidate oncogene. 6 It has been shown to correlate with low-grade, low-stage and papillary tumor growth in primary bladder carcinomas, 9,10 and it has been suggested to play an important role in bladder cancer progression. 11 However, the prognostic significance of cyclin D1 expression in urinary bladder cancer has not yet been determined.…”

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confidence: 99%

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

confidence: 99%

mentioning

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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“…Since inactivation of Rb enhances transcription of p16 INK4a , p16 INK4a may act in normal cells as part of a negative feedback loop to turn off CDK4-cyclin D activity once the cell has passed the G1 restriction point (Serrano et al, 1993;Li et al, 1994;Parry et al, 1995). Thus, inactivation of either p16 INK4a or Rb protein shifts the balance toward continued cell proliferation, as does amplification/overexpression of cyclin D1.Abnormalities of individual components of the Rb/cyclin D1/p16 INK4a pathway have been previously reported in cases of transitional cell carcinoma of the bladder (Cordon-Cardo et al, 1992;Logothetis et al, 1992;Geradts et al, 1995;Gruis et al, 1995;Orlow et al, 1995;Packenham et al, 1995;Williamson et al, 1995;Bringuier et al, 1996;Lee et al, 1997;Shin et al, 1997). In order to assess the overall frequency of G1 checkpoint defects in bladder carcinoma, and to examine the interrelationship between abnormalities in component proteins, we studied a series of 79 transitional cell carcinomas for evidence of cyclin D1 overexpression or loss of Rb or p16 INK4a proteins, using immunohistochemistry.…”

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confidence: 92%

G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder

et al. 1999

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To acquire a neoplastic phenotype, cells must disable multiple regulatory mechanisms including cell cycle control . Abrogation of the G1 cell cycle checkpoint occurs in many malignancies. Key components of the checkpoint include retinoblastoma protein (Rb), cyclin D1 (also known as bcl-1 and PRAD-1), and the cyclin-dependent kinase inhibitor p16 INK4a . In normal cells, the Rb protein acts as a cell cycle brake while in its active, hypophosphorylated state. Cyclin D1 is a short-lived protein with a half-life of 30 min or less. When cyclin D1 is induced in early G1 by mitogenic signals such as growth factors, it binds to and activates the cyclin-dependent kinases CDK4 and CDK6, and these cyclin-kinase complexes then phosphorylate and inactivate the Rb protein, allowing the cell to proceed into S phase (reviewed by Strauss et al, 1995). p16 INK4a binds to CDK-cyclin complexes and blocks phosphorylation of the Rb protein. Since inactivation of Rb enhances transcription of p16 INK4a , p16 INK4a may act in normal cells as part of a negative feedback loop to turn off CDK4-cyclin D activity once the cell has passed the G1 restriction point (Serrano et al, 1993;Li et al, 1994;Parry et al, 1995). Thus, inactivation of either p16 INK4a or Rb protein shifts the balance toward continued cell proliferation, as does amplification/overexpression of cyclin D1.Abnormalities of individual components of the Rb/cyclin D1/p16 INK4a pathway have been previously reported in cases of transitional cell carcinoma of the bladder (Cordon-Cardo et al, 1992;Logothetis et al, 1992;Geradts et al, 1995;Gruis et al, 1995;Orlow et al, 1995;Packenham et al, 1995;Williamson et al, 1995;Bringuier et al, 1996;Lee et al, 1997;Shin et al, 1997). In order to assess the overall frequency of G1 checkpoint defects in bladder carcinoma, and to examine the interrelationship between abnormalities in component proteins, we studied a series of 79 transitional cell carcinomas for evidence of cyclin D1 overexpression or loss of Rb or p16 INK4a proteins, using immunohistochemistry. The p53 status of these tumours was also assessed via immunohistochemistry, since p53 influences cell cycle control through an independent pathway mediated by p21 WAF1/CIP1 (El-Deiry et al, 1993).  Case selection and patient informationMost cases (77 of 79) were drawn from a previously published series (Nguyen et al, 1994) Summary The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16 INK4a , are commonly altered in human malignancies, abrogating cell cycle control. Using immunohistochemistry, we examined 79 invasive transitional cell carcinomas of the urinary bladder treated by cystectomy, for loss of Rb or p16 INK4a protein and for cyclin D1 overexpression. As p53 is also involved in cell cycle control, its expression was studied as well. Rb protein loss occurred in 23/79 cases (29%); it was inversely correlated with loss of p16 INK4a , which occurred i...

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“…Cyclin D1 in particular has been shown to be overexpressed in mantle cell lymphoma and in a variety of carcinomas (19 -31). In transitional carcinoma of the bladder (27) and ductal carcinoma in situ of the breast (45), cyclin D1 expression correlates inversely with the degree of differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Cyclin D1 has especially been shown to be overexpressed in mantle cell lymphomas (20,21) and a variety of carcinomas (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). To date, accumulation of cyclin D3 has been studied less often; its accumulation has also been shown to be associated with an increase in breast tumors and pulmonary carcinomas (32,33).…”

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confidence: 99%

Deregulated Expression of Cell Cycle–Associated Proteins in Solid Pseudopapillary Tumor of the Pancreas

2001

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Solid pseudopapillary tumor of the pancreas was studied in a 20-year-old woman and a 54-year-old woman. In the younger patient, the tumor had metastasized to the liver 8 years after distal pancreatectomy. In both neoplasms, the distinct histologic pattern of solid, pseudopapillary, and degenerative cystic areas was present. Analysis by means of immunohistochemistry revealed a diffuse expression for vimentin, neuron-specific enolase, and a focal positivity for ␣1-antitrypsin, whereas epithelial markers were negative in the tumor of the older patient and only focally expressed in the tumor of the younger patient. Immunohistochemical analysis of cell cycle-associated proteins provided an overexpression of cyclin D1 and cyclin D3 in both tumors, although to varying degrees. In addition, the cyclin-dependent kinase inhibitors p21, and to a lesser extent p27, were up-regulated just as mdm2. There was no accumulation of p53 protein, and Ki67-positive cells were extremely scarce. Analysis of the liver metastases showed an immunoreactive profile similar to that of the primary tumor. The results show a deregulation of the cell cycle with overexpression of cell cycle-activating proteins D1 and D3 and a probably counterbalancing upregulation of the cyclin-dependent kinase inhibitors p21 and p27. The findings may explain the low pool of Ki67-reactive tumor cells and the generally good clinical outcome of these tumors. Whether a more profound dysbalance of the cell cycle regulation is responsible for the development of metastatic disease remains to be clarified.

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Significance of Cyclin D1 Overexpression in Transitional Cell Carcinomas of the Urinary Bladder and its Correlation With Histopathologic Features

Cited by 31 publications

References 0 publications

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

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

G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder

Deregulated Expression of Cell Cycle–Associated Proteins in Solid Pseudopapillary Tumor of the Pancreas

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