Elevated cyclin B2 expression in invasive breast carcinoma is associated with unfavorable clinical outcome

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Abstract

Background

Breast cancer is a potentially fatal malignancy in females despite the improvement in therapeutic techniques. The identification of novel molecular signatures is needed for earlier detection, monitoring effects of treatment, and predicting prognosis. We have previously used microarray analysis to identify differentially expressed genes in aggressive breast tumors. The purpose of the present study was to investigate the prognostic value of the candidate biomarkers CCNB2, ASPM, CDCA7, KIAA0101, and SLC27A2 in breast cancer.

Methods

The expression levels and subcellular localization of the CCNB2, ASPM, CDCA7, KIAA0101, and SLC27A2 proteins were measured using immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Furthermore, the mRNA levels of CCNB2, KIAA0101, and SLC27A2 were subsequently examined by qRT-PCR to validate IHC results. Patient disease-specific survival (DSS) was evaluated in correlation to protein levels using the Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the impact of aberrant protein expression of the candidate biomarkers on patient DSS and to estimate the hazard ratio at 8-year follow-up.

Results

Elevated cytoplasmic CCNB2 protein levels were strongly associated with short-term disease-specific survival of breast cancer patients (≤ 8 years; P<0.001) and with histological tumor type ( P= 0.04). However, no association with other clinicopathological parameters was observed. Multivariate Cox regression analysis specified that CCNB2 protein expression is an independent prognostic marker of DSS in breast cancer. The predictive ability of several classical clinicopathological parameters was improved when used in conjunction with CCNB2 protein expression (C-index = 0.795) in comparison with a model without CCNB2 expression (C-index = 0.698). The protein levels of ASPM, CDCA7, KIAA0101, and SLC27A2 did not correlate with any clinicopathological parameter and had no influence on DSS. However, a significant correlation between the expression of the CCNB2 and ASPM proteins was detected ( P = 0.03).

Conclusion

These findings suggest that cytoplasmic CCNB2 may function as an oncogene and could serve as a potential biomarker of unfavorable prognosis over short-term follow-up in breast cancer.

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Most cited references 35

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Survival model predictive accuracy and ROC curves.

Patrick Heagerty, Yingye Zheng (2005)

The predictive accuracy of a survival model can be summarized using extensions of the proportion of variation explained by the model, or R2, commonly used for continuous response models, or using extensions of sensitivity and specificity, which are commonly used for binary response models. In this article we propose new time-dependent accuracy summaries based on time-specific versions of sensitivity and specificity calculated over risk sets. We connect the accuracy summaries to a previously proposed global concordance measure, which is a variant of Kendall's tau. In addition, we show how standard Cox regression output can be used to obtain estimates of time-dependent sensitivity and specificity, and time-dependent receiver operating characteristic (ROC) curves. Semiparametric estimation methods appropriate for both proportional and nonproportional hazards data are introduced, evaluated in simulations, and illustrated using two familiar survival data sets.

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Cyclin E and survival in patients with breast cancer.

Matthew Callister, Gabriel N Hortobagyi, Katherine L. Tucker … (2002)

Cyclin E, a regulator of the cell cycle, affects the behavior of breast-cancer cells. We investigated whether levels of cyclin E in the tumor correlated with survival among patients with breast cancer. Tumor tissue from 395 patients with breast cancer was assayed for cyclin E, cyclin D1, cyclin D3, and the HER-2/neu oncogene with the use of Western blot analysis. Full-length, low-molecular-weight, and total cyclin E were measured. Immunohistochemical assessments of cyclin E were also made of 256 tumors. We sought correlations between levels of these molecular markers and disease-specific and overall survival. The median follow-up was 6.4 years. A high level of the low-molecular-weight isoforms of cyclin E, as detected by Western blotting, correlated strongly with disease-specific survival whether axillary lymph nodes were negative or positive for metastases (P<0.001). Among 114 patients with stage I breast cancer, none of the 102 patients with low levels of cyclin E in the tumor had died of breast cancer by five years after diagnosis, whereas all 12 patients with a high level of low-molecular-weight cyclin E had died of breast cancer within that period. In multivariate analysis, a high total cyclin E level or high levels of the low-molecular-weight forms of cyclin E were significantly correlated with poor outcome. The hazard ratio for death from breast cancer for patients with high total cyclin E levels as compared with those with low total cyclin E levels was 13.3--about eight times as high as the hazard ratios associated with other independent clinical and pathological risk factors. Levels of total cyclin E and low-molecular-weight cyclin E in tumor tissue, as measured by Western blot assay, correlate strongly with survival in patients with breast cancer. Copyright 2002 Massachusetts Medical Society

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Estimates of the world-wide prevalence of cancer for 25 sites in the adult population.

Paola Pisani, Freddie Bray, D Parkin (2002)

In health services planning, in addition to the basic measures of disease occurrence incidence and mortality, other indexes expressing the demand of care are also required to develop strategies for service provision. One of these is prevalence of the disease, which measures the absolute number, and relative proportion in the population, of individuals affected by the disease and that require some form of medical attention. For most cancer sites, cases surviving 5 years from diagnosis experience thereafter the same survival as the general population, so most of the workload is therefore due to medical acts within these first 5 years. This article reports world-wide estimates of 1-, 2-3- and 4-5-year point prevalence in 1990 in the population aged 15 years or over, and hence describes the number of cancer cases diagnosed between 1986 and 1990 who were still alive at the end of 1990. These estimates of prevalence at 1, 2-3 and 4-5 years are applicable to the evaluation of initial treatment, clinical follow-up and point of cure, respectively, for the majority of cancers. We describe the computational procedure and data sources utilised to obtain these figures and compare them with data published by 2 cancer registries. The highest prevalence of cancer is in North America with 1.5% of the population affected and diagnosed in the previous 5 years (about 0.5% of the population in years 4-5 and 2-3 of follow-up and 0.4% within the first year of diagnosis). This corresponds to over 3.2 million individuals. Western Europe and Australia and New Zealand show very similar percentages with 1.2% and 1.1% of the population affected (about 3.9 and 0.2 million cases respectively). Japan and Eastern Europe form the next batch with 1.0% and 0.7%, followed by Latin America and the Caribbean (overall prevalence of 0.4%), and all remaining regions are around 0.2%. Cancer prevalence in developed countries is very similar in men and women, 1.1% of the sex-specific population, while in developing countries the prevalence is some 25% greater in women than men, reflecting a preponderance of cancer sites with poor survival such as liver, oesophagus and stomach in males. The magnitude of disease incidence is the primary determinant of crude prevalence of cases diagnosed within 1 year so that differences by region mainly reflect variation in risk. In the long-term period however different demographic patterns with long-life expectancy in high-income countries determine a higher prevalence in these areas even for relatively uncommon cancer sites such as the cervix. Copyright 2002 Wiley-Liss, Inc.

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Author and article information

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central

ISSN (Electronic): 1471-2407

Publication date Collection: 2013

Publication date (Electronic): 2 January 2013

Volume: 13

Page: 1

Affiliations

[1 ]Sahlgrenska Cancer Center, Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg SE-41345, Sweden

[2 ]Pathology section, Department of Pathology, Sahlgrenska University Hospital, Gothenburg, SE-41345, Sweden

[3 ]Sahlgrenska Cancer Center, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, SE-41345, Sweden

[4 ]Regional Cancer Centre (West), Western Sweden Health Care Region, Sahlgrenska University Hospital, Gothenburg, SE-41345, Sweden

Article

Publisher ID: 1471-2407-13-1

DOI: 10.1186/1471-2407-13-1

PMC ID: 3545739

PubMed ID: 23282137

SO-VID: 4ef2234a-1f5e-4e70-8c03-c4c600d50eb0

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Elevated cyclin B2 expression in invasive breast carcinoma is associated with unfavorable clinical outcome

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Abstract

Background

Methods

Results

Conclusion

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Karger: Oncology

Most cited references 35

Survival model predictive accuracy and ROC curves.

Cyclin E and survival in patients with breast cancer.

Estimates of the world-wide prevalence of cancer for 25 sites in the adult population.

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