Expression of polo-like kinase in ovarian cancer is associated with histological grade and clinical stage

Takai, Noriyuki; Miyazaki, Tami; Fujisawa, Kayo; Nasu, Kaei; Hamanaka, Ryoji; Miyakawa, Isao

doi:10.1016/s0304-3835(00)00703-5

Cited by 105 publications

(66 citation statements)

References 21 publications

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“…Nevertheless, an additional functional role of PLK isoforms in determining adhesiveness and invasiveness of tumour cells might match with our observation that PLK isoform expression is pronounced at the leading edge of tumour invasion in ovarian carcinoma, which confirmed part of the observations made by Takai et al (2001b).…”

Section: Discussionsupporting

confidence: 90%

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Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma

Weichert

Denkert

Schmidt³

et al. 2004

Br J Cancer

162

131

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The Polo-like kinase (PLK) family comprises three serine/threonine kinases, functionally involved in signal transduction pathways essential for the accomplishment of mitosis in both normal and malignant cells. Moreover, certain PLKs have been functionally linked to cytoskeletal reorganisation. In this study, the expression of PLK1 and PLK3 was determined immunohistochemically in tissue specimen of normal ovaries (n ¼ 9), cystadenomas (n ¼ 17), borderline tumours (n ¼ 13) and ovarian carcinomas (n ¼ 77). PLK 1 and PLK3 expression was low in normal ovarian surface epithelium and borderline tumours, with moderately higher expression levels in cystadenomas. In ovarian carcinomas, 26% of cases were PLK1 positive and 50.6% of cases were PLK3 positive. A positive correlation of both PLK1 and PLK3 expression with indicators of mitotic frequency could be established. The overexpression of either isoenzyme had an impact on patient prognosis with shortened survival time for patients with tumours positive for PLK1 (P ¼ 0.02) and PLK3 (P ¼ 0.02), but only PLK1 expression remained a prognostic factor in multivariate survival analysis (P ¼ 0.03). The results of this study, if interpreted in the context of recently published functional data, suggest that inhibition of PLKs might represent an interesting new targeted approach for chemotherapy of epithelial ovarian cancer. Furthermore, this study suggests that PLK1 is a novel independent prognostic marker in ovarian carcinomas.

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Section: Discussionsupporting

confidence: 90%

“…An earlier study carried out on 17 cases of ovarian carcinoma reported an overexpression of PLK1, which correlated positively with tumour stage and tumour grade (Takai et al, 2001b). In our expanded study population we were not able to reproduce these correlations.…”

Section: Discussionmentioning

confidence: 56%

Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma

Weichert

Denkert

Schmidt³

et al. 2004

Br J Cancer

162

131

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“…The aberrant expression of cell-cycle-associated genes in G2-G3 carcinomas is not a novel observation, and not unexpected in the context of previous work, which has documented upregulation of several cell-cycle genes in ovarian carcinoma, such as polo-like kinase-1 (Takai et al, 2001;Weichert et al, 2004), cdc25a and cdc25b (Broggini et al, 2000), and their correlation with grade/stage and survival, respectively. However, the predictive power of large-scale analyses, such as that presented here, underscores the potential value of being able to monitor thousands of genes across different histologies and grades.…”

Section: Discussionmentioning

confidence: 62%

Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential

et al. 2004

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Profiles of gene transcription have begun to delineate the molecular basis of ovarian cancer, including distinctions between carcinomas of differing histology, tumor progression and patient outcome. However, the similarities and differences among the most commonly diagnosed noninvasive borderline (low malignant potential, LMP) lesions and invasive serous carcinomas of varying grade (G1, G2 and G3) have not yet been explored. Here, we used oligonucleotide arrays to profile the expression of 12 500 genes in a series of 57 predominantly stage III serous ovarian adenocarcinomas from 52 patients, eight with borderline tumors and 44 with adenocarcinomas of varying grade. Unsupervised and supervised analyses showed that LMP lesions were distinct from high-grade serous adenocarcinomas, as might be expected; however, well-differentiated (G1) invasive adenocarcinomas showed a strikingly similar profile to LMP tumors as compared to cancers with moderate (G2) or poor (G3) cellular differentiation, which were also highly similar. Comparative genomic hybridization of an independent cohort of five LMP and 63 invasive carcinomas of varying grade demonstrated LMP and G1 were again similar, exhibiting significantly less chromosomal aberration than G2/G3 carcinomas. A majority of LMP and G1 tumors were characterized by high levels of p21/WAF1, with concomitant expression of cell growth suppressors, gadd34 and BTG-2. In contrast, G2/G3 cancers were characterized by the expression of genes associated with the cell cycle and by STAT-1-, STAT-3/JAK-1/2-induced gene expression. The distinction between the LMP-G1 and G2-G3 groups of tumors was highly correlated to patient outcome (v 2 for equivalence of death rates ¼ 7.681189; P ¼ 0.0056, log-rank test). Our results are consistent with the recent demonstration of a poor differentiation molecular 'meta-signature' in human cancer, and underscore a number of cell-cycle-and STAT-associated targets that may prove useful as points of therapeutic intervention for those patients with aggressive disease.

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“…Plk1 is highly expressed in proliferating cells and in various human tumors including squamous cell cancers of the head and neck, melanomas, gliomas, esophageal, colorectal and lung carcinomas, and endometrial, ovarian and breast cancers (Holtrich et al, 1994;Wolf et al, 1997Wolf et al, , 2000Knecht et al, 1999;Tokumitsu et al, 1999;Dietzmann et al, 2001;Takai et al, 2001;Kneisel et al, 2002;Takahashi et al, 2003). High levels of Plk1 expression in tumors often correlate with poor prognosis.…”

Section: Prospects For Structure-based Drug Designmentioning

confidence: 99%

Structure and function of Polo-like kinases

2005

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Polo-like kinases play critical roles during multiple stages of cell cycle progression. All Polo-like kinases contain an N-terminal Ser/Thr kinase catalytic domain and a Cterminal region that contains one or two Polo-boxes. For Polo-like kinase 1, 2, and 3, and their homologs, the entire C-terminal region, including both Polo-boxes, functions as a single modular phosphoserine/threonine-binding domain known as the Polo-box domain (PBD). In the absence of a bound substrate, the PBD inhibits the basal activity of the kinase domain. Phosphorylation-dependent binding of the PBD to its ligands releases the kinase domain, while simultaneously localizing Polo-like kinases to specific subcellular structures. These observations suggest two different models for how the PBD integrates signals arising from other mitotic kinases to target the activated kinase towards distinct substrates. The recent X-ray crystal structures of the PBD provide insights into the structural basis for PBD function and kinase regulation. Molecular modelling of the structure of the isolated kinase domain reveals a potential basis for motif-dependent substrate specificity.

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Expression of polo-like kinase in ovarian cancer is associated with histological grade and clinical stage

Cited by 105 publications

References 21 publications

Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma

Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma

Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential

Structure and function of Polo-like kinases

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