DNA replication regulation protein Mcm7 as a marker of proliferation in prostate cancer

Abstract

Background: Recent studies have shown that minichromosome maintenance (MCM) proteins (Mcm2-7) may be useful proliferation markers in dysplasia and cancer in various tissues. Aims: To investigate the use of Mcm7 as a proliferation marker in 79 lymph node negative prostate cancers and compare it with Ki-67, a commonly used cell proliferation marker. Methods: The percentage of proliferating cells (proliferation index; PI) was calculated for basal and luminal epithelial cells in benign prostate tissue, prostatic intraepithelial neoplasia (PIN), and epithelial cells in adenocarcinoma. The PI for each biomarker was correlated with the preoperative prostate specific antigen concentration, the Gleason score, surgical resection margin status, and the AJCC pT stage for each patient. Results: The mean PIs for Ki-67 and Mcm7 were: benign luminal epithelium 0.7 and 1.2 and benign basal epithelium 0.8 and 8.2; PIN non-basal epithelium 4.9 and 10.6 and PIN basal epithelium 0.7 and 3.1; adenocarcinoma 9.8 and 22.7, respectively. Mcm7 had a significantly higher mean PI (p,0.0001) than Ki-67 for all cell categories except benign luminal epithelial cells. Mcm7 was a better discriminatory marker of proliferation between benign epithelium, PIN, and invasive adenocarcinoma (p,0.0001) than Ki-67. The drop in Mcm7 mean basal cell PI from benign epithelium to PIN epithelium was significantly larger than for Ki-67 (p,0.0001). Mcm7 had a significantly higher PI than Ki-67 at each risk level. Conclusion: Mcm7 may be a useful proliferation marker in prostatic neoplasia and warrants further evaluation as a complementary tool in the diagnosis of PIN and prostate carcinoma.

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

“…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).…”

“…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 ).…”

Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma

“…With the development of (Meng et al, 2001;Padmanabhan et al, 2004) and ovarian serous neoplasms (Scott et al, 2004) chondrosarcoma (Helfenstein et al, 2004), oligodendroglial tumours (Wharton et al, 2001(Wharton et al, , 2004, oesophageal neoplasm (Going et al, 2002), renal cell carcinoma (Dudderidge et al, 2005), breast cancer (Gonzalez et al, 2004), endometrial carcinoma (Li et al, 2005) and thyroid carcinoma (Guida et al, 2005).…”

“…The clinical relevance of MCM proteins as proliferation markers has been investigated immunohistochemically in several different malignant tumours (Freeman et al, 1999), for example, non-smallcell lung cancer (Ramnath et al, 2001), prostate cancer (Meng et al, 2001;Padmanabhan et al, 2004), oral squamous cell carcinoma (Kodani et al, 2003), chondrosarcoma (Helfenstein et al, 2004), oligodendroglial tumours (Wharton et al, 2001(Wharton et al, , 2004, oesophageal neoplasm (Going et al, 2002), renal cell carcinoma (Dudderidge et al, 2005), breast cancer (Gonzalez et al, 2004), endometrial carcinoma (Li et al, 2005) and thyroid carcinoma (Guida et al, 2005). Most of these studies focused on the detection of MCM2 (Freeman et al, 1999;Chatrath et al, 2003;Davidson et al, 2003;Kodani et al, 2003;Scott et al, 2004).…”

Prognostic significance of Minichromosome maintenance protein 7 and Geminin expression in patients with 109 soft tissue sarcomas

“…MCM proteins were suggested as potential prognostic markers in a variety of human malignancies, including prostate and breast cancer and bronchial adenocarcinoma (19,(27)(28)(29)(30)(31)(32)(33)(34). Overexpression of Minichromosome maintenance protein 7 (MCM7) was reported to actively contribute to tumor formation, progression and malignant conversion.…”