Aberrant Expression of the Cell Cycle Associated Proteins TP53, MDM2, p21, p27, cdk4, Cyclin D1, RB, and EGFR in Cervical Carcinomas

Skomedal, Hanne; Kristensen, Gunnar B.; Lie, A. Kathrine; Holm, Ruth

doi:10.1006/gyno.1999.5346

Cited by 110 publications

(105 citation statements)

References 20 publications

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“…The viral oncoprotein E7 binds to and inhibits the function of the RB protein which in effect bypasses the normal requirement for cyclin D1-CDK in the initiation of cell cycle entry. 18,28 However, as RB is inactivated by HPV, there is a loss of the positive feedback loop and, therefore, downregulation of cyclin D1 despite the concurrent increase in cellular proliferation. Conversely, viral inactivation of the RB protein disrupts the negative feedback loop that normally inhibits p16 protein expression, and hence there is up-regulation of the latter protein even though it is functionally inactive.…”

Section: Discussionmentioning

confidence: 99%

Cyclin D1 immunoreactivity in normal endocervix and diagnostic value in reactive and neoplastic endocervical lesions

Little

Stewart

2010

Modern Pathology

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It may be difficult to distinguish reactive glandular lesions from adenocarcinoma in situ of the uterine cervix, and although several immunohistochemical markers have established value in this diagnostic setting, none is completely reliable. We have noted that neoplastic endocervical lesions often show loss of nuclear cyclin D1 expression in contrast to benign glandular cells. Therefore, we investigated cyclin D1 staining in a series of 64 cervical biopsy specimens including examples of normal and reactive endocervical epithelium, adenocarcinoma in situ, stratified mucin-producing intraepithelial lesions, and invasive adenocarcinoma. Thirteen specimens also included a component of high-grade cervical squamous intraepithelial neoplasia. Normal endocervical epithelium usually expressed cyclin D1, although staining was typically focal, and there was increased immunoreactivity in reactive and metaplastic glandular cells including tubo-endometrioid metaplasia. In contrast, most cases of adenocarcinoma in situ were completely negative and, therefore, cyclin D1 staining distinguished benign from neoplastic epithelial cells. Although focal cyclin D1 expression was observed in 5/19 cases of adenocarcinoma in situ, the staining was associated with more marked cytological atypia precluding confusion with a reactive process. The invasive adenocarcinomas were mainly negative for cyclin D1. However, focal staining was observed in 10/19 cases and was mainly restricted to cells at the deep tumor margin, or to small infiltrative glands and detached cell clusters within the stroma. In conclusion, cyclin D1 can be included within an immunohistochemical panel to aid in the distinction between reactive cervical glandular lesions and adenocarcinoma in situ. The localized distribution of staining within invasive lesions suggests that cyclin D1 up-regulation has a specific role during the progression of some endocervical adenocarcinomas.

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Section: Discussionmentioning

confidence: 99%

Cyclin D1 immunoreactivity in normal endocervix and diagnostic value in reactive and neoplastic endocervical lesions

Little

Stewart

2010

Modern Pathology

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“…Normal cellular proteins that bind to p53 in a manner similar to viral oncoproteins were identified and found to be potential oncogenes (Scheffner et al, 1990;Bargonetti et al, 1991;Debbas and White, 1993;Nees et al, 2001;Cobbs et al, 2003;Dai et al, 2003;Calogero et al, 2004). Proteins implicated in cell cycle regulation may serve as downstream effectors of p53 function (Dulic et al, 1994;Agarwal et al, 1995;de Toledo et al, 1998;Skomedal et al, 1999;Ghimenti et al, 2003). The 1801 monoclonal antibody employed in our study detects a mammalianspecific epitope of both mutant and wild-type p53 protein.…”

Section: Discussionmentioning

confidence: 99%

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

Pardo

Hsu

Zeheb³

et al. 2004

Br J Cancer

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Abnormalities of the p53 tumor-suppressor gene are found in a significant proportion of astrocytic brain tumours. We studied tumour specimens from 74 patients evaluated over 20 years at the Massachusetts General Hospital, where clinical outcome could be determined and sufficient pathologic material was available for immunostaining. p53 expression studies employed an affinity-purified p53 monoclonal antibody, whose specificity was verified in absorption studies and, in a minority of cases, a second antibody recognising a different epitope of p53. Significant overexpression of p53 protein was found in 48% of the 74 tumours included in this series and high levels of expression were associated with higher mortality from astrocytic tumours (Po0.001, log rank). Multivariate analyses revealed that immunohistochemically detected p53 was an independent marker of shortened progression-free and overall actuarial survival in patients with astrocytic tumours, suggesting that increased expression of p53 plays an important role in the pathobiology of these tumours. In a subset of 36 cases, coding regions of the p53 gene were completely sequenced via SSCP and direct DNA sequencing, revealing that overexpression of p53 protein is not always associated with point mutations in conserved exons of the p53 gene. Finally, we confirmed p53 protein expression in early-passage human glioma cell lines of known p53 mutational status and immunostaining scores. Although grade continues to be the strongest prognostic variable, the use of p53 staining as a prognostic indicator, in contrast to mutational DNA analyses, may be a useful adjunct in identifying patients at higher risk of treatment failure.

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“…In most studies, Rb expression appears to be the same in normal cervical epithelium, cervical intraepithelial neoplasia and cervical carcinoma (Skomedal et al, 1999). Some reports (Wrede et al, 1991;Munger et al, 1992) suggest that mutations and LOH of the Rb gene are rare events in cervical cancer and correlate with human papilloma virus (HPV)-negative status, supporting the hypothesis that loss of pRb is required for cervical tumor development and can occur by mutation, LOH or expression of viral proteins capable of complexing and inactivating wild-type cellular proteins.…”

Section: Other Gynecological Malignanciesmentioning

confidence: 99%

RB family members as predictive and prognostic factors in human cancer

2006

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Aberrant Expression of the Cell Cycle Associated Proteins TP53, MDM2, p21, p27, cdk4, Cyclin D1, RB, and EGFR in Cervical Carcinomas

Cited by 110 publications

References 20 publications

Cyclin D1 immunoreactivity in normal endocervix and diagnostic value in reactive and neoplastic endocervical lesions

Cyclin D1 immunoreactivity in normal endocervix and diagnostic value in reactive and neoplastic endocervical lesions

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

RB family members as predictive and prognostic factors in human cancer

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