Abstract 250: Vinculin is a putative amplification target gene at 10q22 in advanced prostate cancer

Abstract

Abstract Patients with advanced prostate cancer are usually treated with androgen withdrawal. Although this therapy is effective at the beginning, nearly all prostate cancers become refractory to it. Approximately 15% of these hormone-refractory prostate cancers contain a genomic amplification at 10q22. Aim of this study was to explore the structure of the 10q22 amplicon and to determine the major driving gene. We applied high-resolution array-CGH using the 244k Agilent microarrays to cell lines harboring 10q22 amplification. We identified a common amplified region (CAR) and silenced each of the 26 genes in this region by an RNAi screen in the prostate cancer cell lines PC-3 and 22rv1. Genes with a significant growth reduction in the 10q22 amplified cell line PC-3 but not in the non-amplified 22rv1 cells were selected as putative candidate genes of this amplicon. They were further investigated in vivo by functional assays and in vitro by immunohistochemical analysis of the protein expression in more than 500 human prostate cancers on a tissue microarray (TMA). We could narrow down the CAR to a region of 5.8 Mb. The siRNA screening experiments revealed Vinculin (VCL) as the most promising candidate gene of this amplicon. Immunohistochemical analysis of the Vinculin protein expression on a TMA enriched for 10q22 amplified prostate cancers showed a strong association between VCL gene amplification and overexpression (p < 0.001). Further analysis of 443 specimens from across all stages of prostate cancer progression showed that Vinculin expression was highest in hormone-refractory prostate cancers, but negative or very low in benign prostatic hyperplasia (p < 0.0001). Notably, high tumor cell proliferation measured by Ki67 expression was significantly associated with high Vinculin expression in prostate cancer (p < 0.0001). Although there are countless reports on Vinculin as a cytoskeletal protein, its role in prostate cancer has previously not been investigated. Our data strongly suggest Vinculin as a major driving gene of the 10q22 amplification in prostate cancer and that Vinculin overexpression might contribute to prostate cancer progression by enhancing tumor cell proliferation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 250.