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DNA replication licensing and cell cycle kinetics of normal and neoplastic breast.
Br J Cancer. 2005 Nov 28; 93(11):1295-300.BJ

Abstract

Mcm2-7 (MCM) proteins are part of the origin licensing machinery that regulates initiation of DNA replication. Geminin is a licensing repressor and prevents reinitiation of DNA replication during S-G2-M phase by blocking reloading of Mcm2-7 at replication origins. Here, we have analysed these replication licensing factors (RLFs) to determine whether the pathway becomes deregulated during mammary carcinogenesis, and have assessed their potential value as prognostic markers. Protein expression profiles were generated for Ki67, Mcm2, geminin, HER-2, ER and PR in a series of reduction mammoplasty (n=18) and breast cancer specimens (n=120), and compared to clinicopathological parameters. A large proportion of epithelial cells of the terminal duct lobular unit reside in a primed 'replication licensed' but not proliferating state. This state is characterised by Mcm2 expression and absence of Ki67 and the S/G2/M marker geminin. In breast cancers, increasing tumour grade is associated with increased Ki67, Mcm2 and geminin expression. The Mcm2/Ki67 ratio decreases through the grades, indicating a shift from a predominantly licensed state to an actively proliferating state. This shift is associated with an increase in the geminin/Ki67 ratio, signifying a shortening of G1 phase in breast cancer cells. Ki67, Mcm2 and the Mcm2/Ki67 ratio are statistically significantly associated with the Nottingham Prognostic Index (NPI), but geminin and the geminin/Ki67 ratio are not. Ki67, Mcm2 and Mcm2/Ki67 are highly correlated with one another, with Mcm2 being the single most important predictor of NPI score (P<0.001). However, only 12% of variation in NPI is explained by Mcm2, as the labelling index for this marker is approaching 100% for many of the high-grade tumours. The origin licensing phenotypes of normal breast and breast cancers therefore relate to their cellular differentiation status, and high-level MCM expression in more poorly differentiated tumours severely constrains their use as prognostic markers in breast cancer.

Authors+Show Affiliations

Department of Pathology, University College London, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16278669

Citation

Shetty, A, et al. "DNA Replication Licensing and Cell Cycle Kinetics of Normal and Neoplastic Breast." British Journal of Cancer, vol. 93, no. 11, 2005, pp. 1295-300.
Shetty A, Loddo M, Fanshawe T, et al. DNA replication licensing and cell cycle kinetics of normal and neoplastic breast. Br J Cancer. 2005;93(11):1295-300.
Shetty, A., Loddo, M., Fanshawe, T., Prevost, A. T., Sainsbury, R., Williams, G. H., & Stoeber, K. (2005). DNA replication licensing and cell cycle kinetics of normal and neoplastic breast. British Journal of Cancer, 93(11), 1295-300.
Shetty A, et al. DNA Replication Licensing and Cell Cycle Kinetics of Normal and Neoplastic Breast. Br J Cancer. 2005 Nov 28;93(11):1295-300. PubMed PMID: 16278669.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - DNA replication licensing and cell cycle kinetics of normal and neoplastic breast. AU - Shetty,A, AU - Loddo,M, AU - Fanshawe,T, AU - Prevost,A T, AU - Sainsbury,R, AU - Williams,G H, AU - Stoeber,K, PY - 2005/11/10/pubmed PY - 2006/1/7/medline PY - 2005/11/10/entrez SP - 1295 EP - 300 JF - British journal of cancer JO - Br. J. Cancer VL - 93 IS - 11 N2 - Mcm2-7 (MCM) proteins are part of the origin licensing machinery that regulates initiation of DNA replication. Geminin is a licensing repressor and prevents reinitiation of DNA replication during S-G2-M phase by blocking reloading of Mcm2-7 at replication origins. Here, we have analysed these replication licensing factors (RLFs) to determine whether the pathway becomes deregulated during mammary carcinogenesis, and have assessed their potential value as prognostic markers. Protein expression profiles were generated for Ki67, Mcm2, geminin, HER-2, ER and PR in a series of reduction mammoplasty (n=18) and breast cancer specimens (n=120), and compared to clinicopathological parameters. A large proportion of epithelial cells of the terminal duct lobular unit reside in a primed 'replication licensed' but not proliferating state. This state is characterised by Mcm2 expression and absence of Ki67 and the S/G2/M marker geminin. In breast cancers, increasing tumour grade is associated with increased Ki67, Mcm2 and geminin expression. The Mcm2/Ki67 ratio decreases through the grades, indicating a shift from a predominantly licensed state to an actively proliferating state. This shift is associated with an increase in the geminin/Ki67 ratio, signifying a shortening of G1 phase in breast cancer cells. Ki67, Mcm2 and the Mcm2/Ki67 ratio are statistically significantly associated with the Nottingham Prognostic Index (NPI), but geminin and the geminin/Ki67 ratio are not. Ki67, Mcm2 and Mcm2/Ki67 are highly correlated with one another, with Mcm2 being the single most important predictor of NPI score (P<0.001). However, only 12% of variation in NPI is explained by Mcm2, as the labelling index for this marker is approaching 100% for many of the high-grade tumours. The origin licensing phenotypes of normal breast and breast cancers therefore relate to their cellular differentiation status, and high-level MCM expression in more poorly differentiated tumours severely constrains their use as prognostic markers in breast cancer. SN - 0007-0920 UR - https://www.unboundmedicine.com/medline/citation/16278669/DNA_replication_licensing_and_cell_cycle_kinetics_of_normal_and_neoplastic_breast_ L2 - http://dx.doi.org/10.1038/sj.bjc.6602829 DB - PRIME DP - Unbound Medicine ER -