Abstract 36: Molecular profiling of prostate cancer xenografts and human specimens reveals overexpression of UBE2C/UBCH10 and activation of aurora kinases in poorly differentiated neuroendocrine carcinoma of the prostate (2011)

Abstract Small cell and large cell neuroendocrine carcinoma belong to the spectrum of poorly differentiated neuroendocrine carcinomas (NECa) of the prostate, characterized by a distinct clinical course. Often unrecognized, they can emerge either de novo or in the castrate-resistant progression of typical acinar adenocarcinoma (AdCa) and are found in 10-20% of men who die of the disease. Although sensitive to chemotherapy, responses are short lived and prognosis is dismal. An understanding of the biology underlying NECa and identification of novel therapeutic targets for this variant are urgently needed. In this study we used xenograft models and tissue specimens obtained from castrate-resistant prostate carcinomas (CRPC) to gain insight into the pathways implicated in the development of the highly aggressive NECa. Xenograft models with features of typical AdCa (n=3) and NECa (n=4) were subjected to gene-expression profiling using Affymetrix HGU133 Plus 2.0. One-way ANOVA was applied to identify differentially expressed probes (DEPs). The Web-based Gene Ontology (GO) Tree Machine was used to examine GO hierarchies. Selected genes were validated by quantitative real-time PCR (qRT-PCR) and Western blotting in the xenografts and by immunohistochemistry in the xenografts, and the tumor specimens of 62 patients with CRPC. Unsupervised hierarchal clustering of the raw data classified the xenografts correctly according to their morphology. Using stringent FDR 0.05, we identified 140 DEPs (0.3%) between the two groups. GO analysis revealed significant enrichment in the “M phase of mitotic cell cycle” biological process subtree (adjP=7.04e-08). Amongst the genes differentially expressed between the two groups, UBE2C, (E2 ubiquitin-conjugating enzyme UBCH10), a member of the anaphase promoting complex (APC), was significantly upregulated in NECa relative to AdCa by qRT-PCR (P=0.003) and immunohistochemistry (P=0.007) in xenografts, and by immunohistochemistry in the CRPC specimens (P&lt;0.001). Similarly, Aurora kinases A and B, proteins with key roles during the G2/M phase of cell cycle, were significantly activated in NECa compared to AdCa xenografts as shown by Western blotting using phospho-Aurora A (Thr288)/Aurora B (Thr232) specific antibodies. In contrast, Cyclin D1, a G1-S phase regulator, was significantly downregulated in NECa xenografts relative to AdCa at the mRNA (P=0.049) and protein level (P=0.003). Cyclin D1 downregulation was also confirmed in the CRPC specimens with NECa relative to those with AdCa morphology (P&lt;0.001). Our findings of UBE2C upregulation and Aurora A and B activation in prostate NECa, suggest a role for G2/M and APC dysregulation in the pathogenesis of NECa and provide the rational to pursue them as therapeutic targets in this prostate cancer variant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 36. doi:10.1158/1538-7445.AM2011-36