Anti-URI1 polyclonal antibody

Purpose: Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for approximately 140,000 deaths annually worldwide. Copy number amplification is frequently associated with the activation of oncogenic drivers in this tumor type, but their cytogenetic complexity and heterogeneity has made it difficult to determine which gene(s) within an amplicon represent(s) the genuine oncogenic driver. We sought to identify amplicon targets by conducting a comprehensive functional analysis of genes located in the regions of amplification in high-grade serous and endometrioid ovarian tumors. Experimental Design: High-throughput siRNA screening technology was used to systematically assess all genes within regions commonly amplified in high-grade serous and endometrioid cancer. We describe the results from a boutique siRNA screen of 272 genes in a panel of 18 ovarian cell lines. Hits identified by the functional viability screen were further interrogated in primary tumor cohorts to determine the clinical outcomes associated with amplification and gene overexpression. Results: We identified a number of genes as critical for cellular viability when amplified, including URI1, PAK4, GAB2, and DYRK1B. Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic use of such genes, particularly URI1 and GAB2, which were significantly associated with survival in 2 independent tumor cohorts. Conclusion: By taking this integrative approach to target discovery, we have streamlined the translation of high-resolution genomic data into preclinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of advanced ovarian tumors. Clin Cancer Res; 19(6); 1411-21. (C) 2013 AACR.

Objectives. Readily apparent cyclin El expression occurs in 50% of HGSOC, but only half are linked to 19q12 locus amplification. The amplified/cyclin E1(hi) to subset has intact BRCA1/2, unfavorable outcome, and is potentially therapeutically targetable. We studied whether non-amplified/cyclin E1(hi) HGSOC has similar characteristics. We also assessed the expression of cyclin El degradation-associated proteins, FBXW7 and USP28, as potential drivers of high cyclin El expression in both subsets. Methods. 262 HGSOC cases were analyzed by in situ hybridization for 19q12 locus amplification and immunohistochemistry for cyclin El, URI1 (another protein encoded by the 19812 locus), FBXW7 and USP28 expression. Tumors were classified by 19q12 amplification status and correlated to cyclin El and URI1 expression, BRCA1/2 germline mutation, FBXW7 and USP28 expression, and clinical outcomes. Additionally, we assessed the relative genomic instability of amplified/cyclin E1(hi) and non-amplified/cyclin E1(hi) groups of HGSOC datasets from The Cancer Genome Atlas. Results. Of the 82 cyclin El hi cases, 43 (52%) were amplified and 39 (48%) were non-amplified. Unlike amplified tumors, non-amplified/cyclin E1(hi) tumor status was not mutually exclusive with gBRCA1/2 mutation. The non-amplified/cyclin E1(hi) group had significantly increased USP28, while the amplified/cyclin E1(hi) cancers had significantly lower FBXW7 expression consistent with a role for both in stabilizing cyclin E1. Notably, only the amplified/cyclin E1(hi) subset was associated with genomic instability and had a worse outcome than nonamplified/cyclin E1(hi) group. Conclusions. Amplified/cyclin E1(hi) and non-amplified/cyclin E1(hi) tumors have different pathological and biological characteristics and clinical outcomes indicating that they are separate subsets of cyclin E1(hi) HGSOC. (C) 2018 Published by Elsevier Inc.