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.

Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression

“…Cep57 insufficiency could drive tumorigenesis in this way. Interestingly, CEP57 insufficiency correlates with tumor growth and metastasis in 2 prostate cancer patient cohorts, and monoallelic mutation was reported in early-onset familial prostate cancers ( 58 , 59 ). Irrespective of the exact mechanism of tumorigenesis, the currently available data warrant future investigations as to whether homozygous and heterozygous carriers of inactivating CEP57 mutations would benefit from intensified cancer screenings, for instance by the use of newly developed multianalyte blood tests ( 60 ).…”

Downstream Neighbor of SON (DONSON) Expression Is Enhanced in Phenotypically Aggressive Prostate Cancers

“…A tissue microarray (TMA) from paraffin-embedded prostate tissue was assessed as described previously [ 23 , 27 , 28 ] ( Supplementary Table S2 ). Paraffin sections of 5 µm thickness were cut and stained with the polyclonal DONSON-antibody (HPA039558, Atlas Antibodies, dilution 1:50; Sigma Aldrich, St. Louis, MO, USA) with the Ventana Benchmark automated staining system (Ventana Medical System, Tuscon, AZ, USA) [ 7 , 29 , 30 , 31 ].…”

“…Two experienced observers independently scored the DONSON staining intensity with a score ranging negative, weak, moderate, or strong DONSON protein expression (score values 0 to 3) as previously described for PCa specimens [ 27 ]. Androgen receptor (AR) expression data, already collected using the immunoreactive score, were also available for a subset of the examined cohort ( n = 62) [ 23 ].…”

“…The androgen receptor (AR) signaling pathway plays a crucial role in the progression of PCa, and nuclear expression of AR predicts an unfavorable clinical outcome and shorter time to the development of castration resistance [22]. Interestingly, in the examined PCa cohort, a strong trend for increased AR expression (studied earlier in [23]) in the DONSON overexpressing subgroup was evident ( Figure 3E). In accordance with this, in both PCa progression cohorts a significant correlation of AR and DONSON mRNA expression was observed (GSE21032: Pearson's r = 0.204, p-value = 0.012; GSE6919: Pearson's r = 0.549, p-value < 0.0001).…”

Replication study: androgen receptor splice variants determine taxane sensitivity in prostate cancer

“…Since the publication of the Registered Report, there have been no additional studies examining the AR signaling profile of LuCaP 86.2 and 23.1 xenograft tumors. However, a study by Mang et al (2015) suggests that high CEP57 expression in prostate cancer tumors is associated with mitotic impairment and, thereby, less aggressive tumor behavior and that the CEP57-induced microtubule stabilization does not affect AR nuclear translocation. This suggests that docetaxel may have other modes of action independent of AR transport inhibition.…”