Overexpression of cell division cycle 7 homolog is associated with gene amplification frequency in breast cancer

Choschzick, Matthias; Lebeau, Annette; Marx, Andreas H.; Tharun, Lars; Terracciano, Luigi; Heilenkötter, Uwe; Jaenicke, Fritz; Bokemeyer, Carsten; Simon, Ronald; Sauter, Guido; Schwarz, Jörg

doi:10.1016/j.humpath.2009.08.008

« Previous Next »Human Pathology
Volume 41, Issue 3 , Pages 358-365, March 2010

Overexpression of cell division cycle 7 homolog is associated with gene amplification frequency in breast cancer

Matthias Choschzick, MD
- Institute of Pathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
Annette Lebeau, MD
- Institute of Pathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
Andreas H. Marx, MD
- Institute of Pathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
Lars Tharun
- Institute of Pathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
Luigi Terracciano, MD
- Institute of Pathology, Cantonal Hospital Basel, 4031 Basel, Switzerland
Uwe Heilenkötter, MD
- Department of Gynaecology, Hospital Itzehoe, 25524 Itzehoe, Germany
Fritz Jaenicke, MD
- Department of Gynaecology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
Carsten Bokemeyer, MD
- Department of Oncology, Hematology, Bone Marrow Transplantation with Section Pneumology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
Ronald Simon, PhD
- Institute of Pathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
- Corresponding author.
Guido Sauter, MD
- Institute of Pathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
Jörg Schwarz, MD
- Department of Gynaecology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany

Received 23 April 2009; received in revised form 25 June 2009; accepted 4 August 2009. published online 09 November 2009.

Summary

Cell division cycle 7 is a widely expressed protein kinase implicated in cell division, cell cycle checkpoint mechanisms, and cancer progression. To determine the relationship of cell division cycle 7 protein expression with tumor phenotype, molecular features and prognosis, 2197 highly characterized breast carcinomas were analyzed on a tissue microarray. Detectable cell division cycle 7 expression was found in 1088 (57%) of breast cancer specimens and 228 (11.9%) exhibited a moderate or strong expression. High levels of cell division cycle 7 expression were significantly related to medullary histotype (P < .0001); high tumor grade (P < .0001); negative estrogen receptor status (P < .0001); high Ki67 expression level (P < .0001); p53 and p16 overexpression (P < .0001); and amplification of HER2 (P < .0001), c-myc (P < .0001), MDM2 (P = .043), CCND1 (P = .0084), and ESR1 (P = .0012) as well as with the number of amplified genes (P < .0001). There was also a tendency towards worse prognosis in cell division cycle 7 positive as compared to negative breast cancers. The relationship between cell division cycle 7 and number of amplifications was independent from tumor proliferation raising the possibility of a direct influence of cell division cycle 7 expression for amplification development. In conclusion, cell division cycle 7 is a replication associated protein with relationships to gene amplification and genomic instability in breast carcinomas. These data support the potential utility of newly developed small molecule cell division cycle 7 inhibitors as a therapeutic alternative in at least a subset of breast carcinomas.