title: Prognostic Significance and Functional Role of CEP57 in Prostate Cancer.
abstract: We have recently shown that centrosomal protein 57 (CEP57) is overexpressed in a subset of human prostate cancers. CEP57 is involved in intracellular transport processes, and its overexpression causes mitotic defects as well as abnormal microtubule nucleation and bundling. In the present study, we further characterized the prognostic and functional role of CEP57 in prostate cancer. Unexpectedly, we found that high CEP57 expression is an independent prognostic factor for a more favorable biochemical recurrence-free survival in two large patient cohorts. To reconcile this finding with the ability of CEP57 to cause cell division errors and thus potentially promote malignant progression, we hypothesized that alterations of microtubule-associated transport processes, in particular nuclear translocation of the androgen receptor (AR), may play a role in our finding. However, CEP57 overexpression and microtubule bundling had, surprisingly, no effect on the nuclear translocation of the AR. Instead, we found a significant increase of cells with disarranged microtubules and a cellular morphology suggestive of a cytokinesis defect. Because mitotic dysfunction leads to a reduced daughter cell formation, it can explain the survival benefit of patients with increased CEP57 expression. In contrast, we show that a reduced expression of CEP57 is associated with malignant growth and metastasis. Taken together, our findings underscore that high CEP57 expression is associated with mitotic impairment and less aggressive tumor behavior. Because the CEP57-induced microtubule stabilization had no detectable effect on AR nuclear translocation, our results furthermore suggest that microtubule-targeting therapeutics used in advanced prostate cancer such as docetaxel may have modes of action that are at least in part independent of AR transport inhibition.
authors.affiliation: Molecular Urooncology, Department of Urology, Medical Faculty Heidelberg, University of Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Mang
authors.affiliation: Molecular Urooncology, Department of Urology, Medical Faculty Heidelberg, University of Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Korzeniewski
authors.affiliation: Institute of Pathology, University of Bonn School of Medicine, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
authors.forename: Dimo
authors.initials: D
authors.lastname: Dietrich
authors.affiliation: Institute of Pathology, University of Bonn School of Medicine, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Sailer
authors.affiliation: Molecular Urooncology, Department of Urology, Medical Faculty Heidelberg, University of Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
authors.forename: Yanis
authors.initials: Y
authors.lastname: Tolstov
authors.affiliation: Molecular Urooncology, Department of Urology, Medical Faculty Heidelberg, University of Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
authors.forename: Sam
authors.initials: S
authors.lastname: Searcy
authors.affiliation: Department of Urology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany.
authors.forename: Jost
authors.initials: J
authors.lastname: von Hardenberg
authors.affiliation: Pathology Network of the University Hospital of Lübeck and Leibniz Research Center Borstel, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Institute of Pathology, University of Bonn School of Medicine, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.affiliation: Institute of Pathology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx
authors.affiliation: Institute of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
authors.affiliation: Institute of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany; Tissue Bank of the National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 220/221, D-69120 Heidelberg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.affiliation: National Center for Tumor Diseases (NCT), Department of Medical Oncology, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Grüllich
authors.affiliation: Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Popeneciu
authors.affiliation: Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Pahernik
authors.affiliation: Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Hadaschik
authors.affiliation: Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hohenfellner
authors.affiliation: Molecular Urooncology, Department of Urology, Medical Faculty Heidelberg, University of Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany; Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany. Electronic address: stefan.duensing@med.uni-heidelberg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing