Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

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

Authors: Emman Shubbar, Anikó Kovács, Shahin Hajizadeh, Toshima Z Parris, Szilárd Nemes, Katrin Gunnarsdóttir, Zakaria Einbeigi, Per Karlsson, Khalil Helou

Published in: BMC Cancer | Issue 1/2013

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Pisani P, Bray F, Parkin DM: Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. Int J Cancer. 2002, 97 (1): 72-81. 10.1002/ijc.1571.CrossRefPubMed
2.
Khleif SN, Doroshow JH, Hait WN: AACR-FDA-NCI Cancer Biomarkers Collaborative consensus report: advancing the use of biomarkers in cancer drug development. Clin Cancer Res. 2010, 16 (13): 3299-3318. 10.1158/1078-0432.CCR-10-0880.CrossRefPubMed
3.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, et al: Molecular portraits of human breast tumours. Nature. 2000, 406 (6797): 747-752. 10.1038/35021093.CrossRefPubMed
4.
Masood S: Prognostic/predictive factors in breast cancer. Clin Lab Med. 2005, 25 (4): 809-825. 10.1016/j.cll.2005.08.012.CrossRefPubMed
5.
Andreopoulou E, Hortobagyi GN: Prognostic factors in metastatic breast cancer: successes and challenges toward individualized therapy. J Clin Oncol. 2008, 26 (22): 3660-3662. 10.1200/JCO.2008.16.1026.CrossRefPubMed
6.
Socialstyrelsen: Cancer incidence in Sweden 2010. 2010
7.
Parris TZ, Danielsson A, Nemes S, Kovacs A, Delle U, Fallenius G, Mollerstrom E, Karlsson P, Helou K: Clinical implications of gene dosage and gene expression patterns in diploid breast carcinoma. Clin Cancer Res. 2010, 16 (15): 3860-3874. 10.1158/1078-0432.CCR-10-0889.CrossRefPubMed
8.
Elston CW, Ellis IO: Pathological prognostic factors in breast cancer, I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 2002, 41 (3A): 154-161.CrossRefPubMed
9.
Draetta G, Luca F, Westendorf J, Brizuela L, Ruderman J, Beach D: Cdc2 protein kinase is complexed with both cyclin A and B: evidence for proteolytic inactivation of MPF. Cell. 1989, 56 (5): 829-838.CrossRefPubMed
10.
van der Voet M, Berends CW, Perreault A, Nguyen-Ngoc T, Gonczy P, Vidal M, Boxem M, van den Heuvel S: NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote meiotic spindle rotation independently of cortical LIN-5/GPR/Galpha. Nat Cell Biol. 2009, 11 (3): 269-277. 10.1038/ncb1834.CrossRefPubMed
11.
Higgins J, Midgley C, Bergh AM, Bell SM, Askham JM, Roberts E, Binns RK, Sharif SM, Bennett C, Glover DM, et al: Human ASPM participates in spindle organisation, spindle orientation and cytokinesis. BMC Cell Biol. 2010, 11: 85-10.1186/1471-2121-11-85.CrossRefPubMedPubMedCentral
12.
Simpson F, Lammerts Van Bueren K, Butterfield N, Bennetts JS, Bowles J, Adolphe C, Simms LA, Young J, Walsh MD, Leggett B, et al: The PCNA-associated factor KIAA0101/p15(PAF) binds the potential tumor suppressor product p33ING1b. Exp Cell Res. 2006, 312 (1): 73-85. 10.1016/j.yexcr.2005.09.020.CrossRefPubMed
13.
Osthus RC, Karim B, Prescott JE, Smith BD, McDevitt M, Huso DL, Dang CV: The Myc target gene JPO1/CDCA7 is frequently overexpressed in human tumors and has limited transforming activity in vivo. Cancer Res. 2005, 65 (13): 5620-5627. 10.1158/0008-5472.CAN-05-0536.CrossRefPubMedPubMedCentral
14.
Stahl A: A current review of fatty acid transport proteins (SLC27). Pflugers Arch. 2004, 447 (5): 722-727. 10.1007/s00424-003-1106-z.CrossRefPubMed
15.
Helou K, Wallenius V, Qiu Y, Ohman F, Stahl F, Klinga-Levan K, Kindblom LG, Mandahl N, Jansson JO, Levan G: Amplification and overexpression of the hepatocyte growth factor receptor (HGFR/MET) in rat DMBA sarcomas. Oncogene. 1999, 18 (21): 3226-3234. 10.1038/sj.onc.1202658.CrossRefPubMed
16.
Shubbar E, Vegfors J, Carlstrom M, Petersson S, Enerback C: Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation. Breast Cancer Res Treat. 2011, 134 (1): 71-80.CrossRefPubMed
17.
Heagerty PJ, Zheng Y: Survival model predictive accuracy and ROC curves. Biometrics. 2005, 61 (1): 92-105. 10.1111/j.0006-341X.2005.030814.x.CrossRefPubMed
18.
Sutherland RL, Musgrove EA: Cyclins and breast cancer. J Mammary Gland Biol Neoplasia. 2004, 9 (1): 95-104.CrossRefPubMed
19.
Keyomarsi K, Tucker SL, Buchholz TA, Callister M, Ding Y, Hortobagyi GN, Bedrosian I, Knickerbocker C, Toyofuku W, Lowe M, et al: Cyclin E and survival in patients with breast cancer. N Engl J Med. 2002, 347 (20): 1566-1575. 10.1056/NEJMoa021153.CrossRefPubMed
20.
Sutherland RL, Musgrove EA: Cyclin D1 and mammary carcinoma: new insights from transgenic mouse models. Breast cancer research: BCR. 2002, 4 (1): 14-17. 10.1186/bcr411.CrossRefPubMed
21.
Baldini E, Camerini A, Sgambato A, Prochilo T, Capodanno A, Pasqualetti F, Orlandini C, Resta L, Bevilacqua G, Collecchi P: Cyclin A and E2F1 overexpression correlate with reduced disease-free survival in node-negative breast cancer patients. Anticancer Res. 2006, 26 (6B): 4415-4421.PubMed
22.
Petri ET, Errico A, Escobedo L, Hunt T, Basavappa R: The crystal structure of human cyclin B. Cell Cycle. 2007, 6 (11): 1342-1349. 10.4161/cc.6.11.4297.CrossRefPubMed
23.
Wu T, Zhang X, Huang X, Yang Y, Hua X: Regulation of cyclin B2 expression and cell cycle G2/m transition by menin. J Biol Chem. 2010, 285 (24): 18291-18300. 10.1074/jbc.M110.106575.PubMedPubMedCentral
24.
Hofmann HS, Hansen G, Burdach S, Bartling B, Silber RE, Simm A: Discrimination of human lung neoplasm from normal lung by two target genes. Am J Respir Crit Care Med. 2004, 170 (5): 516-519. 10.1164/rccm.200407-127OC.CrossRefPubMed
25.
Stav D, Bar I, Sandbank J: Usefulness of CDK5RAP3, CCNB2, and RAGE genes for the diagnosis of lung adenocarcinoma. Int J Biol Markers. 2007, 22 (2): 108-113.PubMed
26.
Park SH, Yu GR, Kim WH, Moon WS, Kim JH, Kim DG: NF-Y-dependent cyclin B2 expression in colorectal adenocarcinoma. Clin Cancer Res. 2007, 13 (3): 858-867. 10.1158/1078-0432.CCR-06-1461.CrossRefPubMed
27.
De Martino I, Visone R, Wierinckx A, Palmieri D, Ferraro A, Cappabianca P, Chiappetta G, Forzati F, Lombardi G, Colao A, et al: HMGA proteins up-regulate CCNB2 gene in mouse and human pituitary adenomas. Cancer Res. 2009, 69 (5): 1844-1850. 10.1158/0008-5472.CAN-08-4133.CrossRefPubMed
28.
Mo ML, Chen Z, Li J, Li HL, Sheng Q, Ma HY, Zhang FX, Hua YW, Zhang X, Sun DQ, et al: Use of serum circulating CCNB2 in cancer surveillance. Int J Biol Markers. 2010, 25 (4): 236-242.PubMed
29.
Veer LJ V't, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002, 415 (6871): 530-536. 10.1038/415530a.CrossRef
30.
Fish JL, Kosodo Y, Enard W, Paabo S, Huttner WB: Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells. Proc Natl Acad Sci U S A. 2006, 103 (27): 10438-10443. 10.1073/pnas.0604066103.CrossRefPubMedPubMedCentral
31.
Paramasivam M, Chang YJ, LoTurco JJ: ASPM and citron kinase co-localize to the midbody ring during cytokinesis. Cell Cycle. 2007, 6 (13): 1605-1612. 10.4161/cc.6.13.4356.CrossRefPubMed
32.
Horvath S, Zhang B, Carlson M, Lu KV, Zhu S, Felciano RM, Laurance MF, Zhao W, Qi S, Chen Z, et al: Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Proc Natl Acad Sci U S A. 2006, 103 (46): 17402-17407. 10.1073/pnas.0608396103.CrossRefPubMedPubMedCentral
33.
Lin SY, Pan HW, Liu SH, Jeng YM, Hu FC, Peng SY, Lai PL, Hsu HC: ASPM is a novel marker for vascular invasion, early recurrence, and poor prognosis of hepatocellular carcinoma. Clin Cancer Res. 2008, 14 (15): 4814-4820. 10.1158/1078-0432.CCR-07-5262.CrossRefPubMed
34.
Vulcani-Freitas TM, Saba-Silva N, Cappellano A, Cavalheiro S, Marie SK, Oba-Shinjo SM, Malheiros SM, de Toledo SR: ASPM gene expression in medulloblastoma. Childs Nerv Syst. 2011, 27 (1): 71-74. 10.1007/s00381-010-1252-5.CrossRefPubMed
35.
Bruning-Richardson A, Bond J, Alsiary R, Richardson J, Cairns DA, McCormack L, Hutson R, Burns P, Wilkinson N, Hall GD, et al: ASPM and microcephalin expression in epithelial ovarian cancer correlates with tumour grade and survival. Br J Cancer. 2011, 104 (10): 1602-1610. 10.1038/bjc.2011.117.CrossRefPubMedPubMedCentral
36.
Wu SC, Chang SC, Wu HY, Liao PJ, Chang MF: Hepatitis C virus NS5A protein down-regulates the expression of spindle gene Aspm through PKR-p38 signaling pathway. J Biol Chem. 2008, 283 (43): 29396-29404. 10.1074/jbc.M802821200.CrossRefPubMedPubMedCentral
37.
Hodgson JG, Yeh RF, Ray A, Wang NJ, Smirnov I, Yu M, Hariono S, Silber J, Feiler HS, Gray JW, et al: Comparative analyses of gene copy number and mRNA expression in glioblastoma multiforme tumors and xenografts. Neuro Oncol. 2009, 11 (5): 477-487. 10.1215/15228517-2008-113.CrossRefPubMedPubMedCentral
38.
Bikeye SN, Colin C, Marie Y, Vampouille R, Ravassard P, Rousseau A, Boisselier B, Idbaih A, Calvo CF, Leuraud P, et al: ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target. Cancer Cell Int. 2010, 10: 1-10.1186/1475-2867-10-1.CrossRefPubMedPubMedCentral
39.
Yu P, Huang B, Shen M, Lau C, Chan E, Michel J, Xiong Y, Payan DG, Luo Y: p15(PAF), a novel PCNA associated factor with increased expression in tumor tissues. Oncogene. 2001, 20 (4): 484-489. 10.1038/sj.onc.1204113.CrossRefPubMed
40.
Notterman DA, Alon U, Sierk AJ, Levine AJ: Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissue examined by oligonucleotide arrays. Cancer Res. 2001, 61 (7): 3124-3130.PubMed
41.
Petroziello J, Yamane A, Westendorf L, Thompson M, McDonagh C, Cerveny C, Law CL, Wahl A, Carter P: Suppression subtractive hybridization and expression profiling identifies a unique set of genes overexpressed in non-small-cell lung cancer. Oncogene. 2004, 23 (46): 7734-7745. 10.1038/sj.onc.1207921.CrossRefPubMed
42.
Kato T, Daigo Y, Aragaki M, Ishikawa K, Sato M, Kaji M: Overexpression of KIAA0101 predicts poor prognosis in primary lung cancer patients. Lung Cancer. 2012, 75 (1): 110-118. 10.1016/j.lungcan.2011.05.024.CrossRefPubMed
43.
Kais Z, Barsky SH, Mathsyaraja H, Zha A, Ransburgh DJ, He G, Pilarski RT, Shapiro CL, Huang K, Parvin JD: KIAA0101 interacts with BRCA1 and regulates centrosome number. Mol Cancer Res. 2011, 9 (8): 1091-1099. 10.1158/1541-7786.MCR-10-0503.CrossRefPubMedPubMedCentral
44.
Ideker T, Thorsson V, Ranish JA, Christmas R, Buhler J, Eng JK, Bumgarner R, Goodlett DR, Aebersold R, Hood L: Integrated genomic and proteomic analyses of a systematically perturbed metabolic network. Science. 2001, 292 (5518): 929-934. 10.1126/science.292.5518.929.CrossRefPubMed
45.
Cox B, Kislinger T, Emili A: Integrating gene and protein expression data: pattern analysis and profile mining. Methods. 2005, 35 (3): 303-314. 10.1016/j.ymeth.2004.08.021.CrossRefPubMed
46.
Yi Y, Nandana S, Case T, NElston C, Radmilovic T, Matusik RJ, Tsuchiya KD: Candidate metastasis suppressor genes uncovered by array comparative genomic hybridization in a mouse allograft model of prostate cancer. Mol Cytogenet. 2009, 2: 18-10.1186/1755-8166-2-18.CrossRefPubMedPubMedCentral
Metadata
Title
Elevated cyclin B2 expression in invasive breast carcinoma is associated with unfavorable clinical outcome
Authors
Emman Shubbar
Anikó Kovács
Shahin Hajizadeh
Toshima Z Parris
Szilárd Nemes
Katrin Gunnarsdóttir
Zakaria Einbeigi
Per Karlsson
Khalil Helou
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-1

Other articles of this Issue 1/2013

BMC Cancer 1/2013 Go to the issue

Research article

Heparan sulfate mediates trastuzumab effect in breast cancer cells

Study protocol

Influence of a six month endurance exercise program on the immune function of prostate cancer patients undergoing Antiandrogen- or Chemotherapy: design and rationale of the ProImmun study

Research article

Estimating the lifelong health impact and financial burdens of different types of lung cancer

Research article

Context-dependent interpretation of the prognostic value of BRAF and KRAS mutations in colorectal cancer

Research article

Quality of life of Bahraini women with breast cancer: a cross sectional study

Research article

Early versus deferred androgen suppression therapy for patients with lymph node-positive prostate cancer after local therapy with curative intent: a systematic review
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits