Minichromosome Maintenance Protein 2 Is a Strong Independent Prognostic Marker in Breast Cancer

Gonzalez, Michael; Pinder, Sarah; Callagy, Grace; Vowler, Sarah L.; Morris, Lydia; Bird, K; Bell, Jane M.; Laskey, Ronald A.; Coleman, Nicholas

doi:10.1200/jco.2003.04.121

Cited by 138 publications

(146 citation statements)

References 40 publications

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“…Moreover, Mcm2-7 expression levels are powerful prognostic indicators in diverse tumour types, including cancers of the lung, breast, kidney, bladder, prostate and ovary [71][72][73][74][75][76][77]. This finding is consistent with large-scale meta-analysis of cancer microarray data, which identified up-regulation of the MCM2-6 genes as a component of poor prognostic signatures [78].…”

Section: Dna Replication Licensing and Cancersupporting

confidence: 71%

The cell cycle and cancer

Williams

Stoeber

2011

The Journal of Pathology

569

406

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Deregulation of the cell cycle underlies the aberrant cell proliferation that characterizes cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades, cancer genetics has shown that hyperactivating mutations in growth signalling networks, coupled to loss of function of tumour suppressor proteins, drives oncogenic proliferation. Gene expression profiling of these complex and redundant mitogenic pathways to identify prognostic and predictive signatures and their therapeutic targeting has, however, proved challenging. The cell cycle machinery, which acts as an integration point for information transduced through upstream signalling networks, represents an alternative target for diagnostic and therapeutic interventions. Analysis of the DNA replication initiation machinery and mitotic engine proteins in human tissues is now leading to the identification of novel biomarkers for cancer detection and prognostication, and is providing target validation for cell cycle-directed therapies.

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Section: Dna Replication Licensing and Cancersupporting

confidence: 71%

The cell cycle and cancer

Williams

Stoeber

2011

The Journal of Pathology

569

406

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“…RLFs, which form the core of the initiation machinery, act as relay stations coupling growth regulatory and DNA damage response pathways to chromosomal replication. We and others have demonstrated that dysregulation of the replication Ki67 Geminin P C 3 -P a r e n t a l P C 3 -e m p t y v e c t o r P C 3 -E R K 5 P C 3 -P a r e n t a l P C 3 -e m p t y v e c t o r initiation machinery is an early event in tumourigenesis and that the Mcm2-7 RLFs are powerful diagnostic and prognostic markers in a wide range of tumour types (Williams et al, 1998Stoeber et al, 1999;Wharton et al, 2001Wharton et al, , 2004Davies et al, 2002;Going et al, 2002;Stoeber et al, 2002;Gonzalez et al, 2003;Kruger et al, 2003;Padmanabhan et al, 2004;Dudderidge et al, 2005;Korkolopoulou et al, 2005;Shetty et al, 2005). Recent reports have shown that the MEK5/ERK5 pathway is implicated in the regulation of cell proliferation, and that increased MEK5/ERK5 signalling results in increased cell proliferation, invasion and metastatic spread during prostate carcinogenesis Mehta et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The constituents of the pre-RC can be regarded as relay stations coupling growth regulatory pathways with DNA replication . We and others have demonstrated in a range of different tumour types that dysregulation of the MCM proteins is an early event in tumourigenesis and have exploited these biomarkers in primary diagnosis, tumour surveillance and prognosis (Williams et al, 1998Stoeber et al, 1999Stoeber et al, , 2002Wharton et al, 2001Wharton et al, , 2004Davies et al, 2002;Going et al, 2002;Gonzalez et al, 2003;Kruger et al, 2003;Padmanabhan et al, 2004;Dudderidge et al, 2005;Korkolopoulou et al, 2005;Shetty et al, 2005). These studies have established that the superior sensitivity of MCM proteins over the standard proliferation marker Ki67 resides in the fact that these biomarkers identify not only cycling cells but also non-cycling cells with proliferative potential ).…”

mentioning

confidence: 99%

Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer

et al. 2007

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Activation of mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) growth signalling is coupled to increased cell proliferation in prostate cancer (PCa). Dysregulation of the DNA replication licensing pathway, a critical step in growth control downstream of transduction signalling pathways, is associated with development of PCa. In this study we have investigated linkages between the MEK5/ERK5 pathway and DNA replication licensing during prostate carcinogenesis. The effects of increased MEK5/ERK5 signalling on the expression of replication licensing factors Mcm2 and geminin and the proliferation marker Ki67 were studied in an ecdysone-inducible system expressing a constitutively activated mutant of MEK5 in EcR293 cells and in stable ERK5 over-expressing PC3 clones. In parallel, expression of these biomarkers in PCa biopsy specimens (n ¼ 58) was studied and compared to clinicopathological parameters. In both in vitro systems induction of MEK5 expression resulted in increased levels of phosphorylated ERK5 and Mcm2, geminin and Ki67 proteins. In PCa specimens average Mcm2 expression was greater than Ki67 and geminin expression (median labelling index (LI) 36.7, 18.1, and 3.4% respectively), consistent with their differential expression according to growth status (Po0.0001). Mcm2, geminin and Ki67 expression were significantly associated with Gleason grade (P ¼ 0.0002, P ¼ 0.0003, P ¼ 0.004); however there was no link with T or M stage. There was a significant relationship between increasing ERK5 expression and increasing Mcm2 (P ¼ 0.003) and Ki67 (P ¼ 0.009) expression, with non-significant trends seen with increasing MEK5 expression. There were significant associations between Gleason grade and the number of cells traversing G1 phase (Ki67 LI -geminin LI ; (P ¼ 0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2 LI -Ki67 LI ; (P ¼ 0.01)) and accelerated cell cycle progression (geminin LI /Ki67 LI ; (P ¼ 0.005)), all indicative of a shift towards increasing proliferative potential. While Mcm2 and Ki67 were both prognostic factors on univariate analysis, only Mcm2 remained an independent prognostic marker on multivariate analysis. Taken together, our data show that induction of MEK5/ERK5 signalling is linked to activation of the DNA replication licensing pathway in PCa, and that the strong prognostic value of MCM proteins may result from their function as relay stations coupling growth regulatory pathways to genome duplication.

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“…This novel approach thus allows a detailed assessment of tumour cell cycle kinetics that can be routinely applied to archival specimens. We and others have already demonstrated that the MCM replication-licensing factors can be exploited as prognostic markers in cancer diagnosis (Meng et al, 2001;Ramnath et al, 2001;Wharton et al, 2001;Gonzalez et al, 2003;Kruger et al, 2003). Analysis of a range of different tumour types including glial tumours is now in progress to determine whether the Geminin origin-licensing repressor and/or the Geminin/Ki67 ratio can be exploited as independent predictors of disease-free survival.…”

Section: Discussionmentioning

confidence: 99%

DNA replication licensing and cell cycle kinetics of oligodendroglial tumours

et al. 2004

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The convergence point of growth-signalling pathways that control cell proliferation is the initiation of genome replication, the core of which is the assembly of pre-replicative complexes (pre-RCs), resulting in chromatin being 'licensed' for DNA replication in the subsequent S phase. The Mcm2 -7 complex is a core constituent of the pre-RC, whose recruitment to replication origins is dependent on the Cdt1 loading factor. Geminin is a potent inhibitor of the initiation of DNA replication by preventing Mcm2 -7 assembly at origins via its interaction with Cdt1, ensuring genomic integrity through suppression of re-initiation events in S phase. Here we investigate the regulation of Ki67, Mcm2, p21, caspase 3 and Geminin in a series of 55 oligodendrogliomas to provide an integrated picture of how cellular proliferation and programmed cell death are dysregulated in these tumours. Geminin does not behave as an inhibitor of cell proliferation, its labelling index rising with increasing growth fraction as defined by Ki67 or Mcm2 expression. Geminin is expressed in a higher proportion of cells in higher grade tumours (Po0.001) and shows a strong correlation to proliferation and replication licensing (Po0.01), but not apoptosis. Increasing tumour anaplasia is not associated with loss of Geminin. Importantly, the G1 phase of the proliferative cell cycle, as assessed by the Geminin/Ki67 ratio, shortens with increasing anaplasia, providing new potential algorithms for prognostic assessment. Origin licensing proteins thus provide powerful novel tools for assessment of tumour cell cycle kinetics in routinely processed surgical biopsy material.

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Minichromosome Maintenance Protein 2 Is a Strong Independent Prognostic Marker in Breast Cancer

Abstract: Mcm-2 may be of utility as a prognostic marker to refine the prediction of outcome in breast cancer, for example when combined with parameters currently used in the NPI.

Cited by 138 publications

References 40 publications

The cell cycle and cancer

The cell cycle and cancer

Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer

DNA replication licensing and cell cycle kinetics of oligodendroglial tumours

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