Overexpression of cell division cycle 7 homolog is associated with gene amplification frequency in breast cancer.
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.
Choschzick
Matthias
M
Institute of Pathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.
Lebeau
Annette
A
Marx
Andreas H
AH
Tharun
Lars
L
Terracciano
Luigi
L
Heilenkötter
Uwe
U
Jaenicke
Fritz
F
Bokemeyer
Carsten
C
Simon
Ronald
R
Sauter
Guido
G
Schwarz
Jörg
J
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D016009:Chi-Square Distribution; D018450:Disease Progression; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D046888:Tissue Array Analysis
D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases